Pyrazolopyrimidine derivatives useful as inhibitors of Bruton&#39;s tyrosine kinase

ABSTRACT

This invention relates to compounds of formula (I). The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton&#39;s tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton&#39;s tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.

RELATED APPLICATIONS

This application is a national phase filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB2015/051719, filed Jun. 11, 2015,which claims the benefit of and priority to United Kingdom PatentApplication No. GB1410430.1, filed Jun. 11, 2014, the contents of whichapplications are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compounds. More specifically, the inventionrelates to compounds useful as kinase inhibitors, along with processesto prepare the compounds and uses of the compounds. Specifically, theinvention relates to inhibitors of Bruton's tyrosine kinase (BTK).

BACKGROUND

Kinases are a class of enzyme that control the transfer of phosphategroups from phosphate donor groups, for example ATP, to specificsubstrates. Protein kinases are a subset of kinases and BTK is one suchprotein kinase.

BTK is a member of the src-related Tec family of cytoplasmic tyrosinekinases. BTK plays a key role in the signalling pathways of B-cells,affecting B-cell development, activation, signalling and survival. Incertain malignancies, B-cells overexpress BTK. These malignant B-cellsand the overexpression of BTK by the cells has been associated with theincreased proliferation and survival of tumor cells. Inhibition of BTKaffects the B-cell signalling pathways, preventing activation of B-cellsand inhibiting the growth of malignant B-cells.

A number of clinical trials have shown that BTK inhibitors are affectiveagainst cancer.

BTK inhibitors that have been reported are Ibrutinib (PCI-32765) andCC-292. CC-292 is manufactured by Avila Pharmaceuticals who have filedapplications for protein kinases published as WO 2011/090760 and WO2009/158571. Ibrutinib is disclosed in at least US 2008/0076921. Studieson Ibrutinib have found that it possesses a number of undesirablepharmacological features. For example, Ibrutinib is poorly soluble andis a weak inhibitor of hERG. Furthermore, rat pharmacokinetic data hasshown that Ibrutinib has a low estimated fraction absorbed, poorbioavailability and a high clearance rate from the body, with a terminalT_(1/2) of 1.5 hours.

Since Ibrutinib was first disclosed there have been a number of patentapplications concerned with structures closely related to Ibrutinib, forexample see WO 2012/158843, WO 2012/158764, WO 2011/153514, WO2011/046964, US 2010/0254905, US 2010/0144705, U.S. Pat. No. 7,718,662,WO, 2008/054827 and WO 2008/121742.

Most recently, WO 2013/010136 disclosed BTK inhibitors with a relatedstructure to Ibrutinib.

Known BTK inhibitors, e.g. Ibrutinib, have presented gastrointestinalside effects. These side effects have been attributed to the EGFRinhibitory activity of the BTK inhibitors. It is therefore desirable tohave a BTK inhibitor with high BTK inhibition and low EGFR inhibition toreduce or avoid the gastrointestinal side effects. Such high BTKinhibition and low EGFR inhibition is readily identified by a large“Fold Selectivity” value.

Therefore, an aim of the present invention is to provide BTK inhibitors.In addition the invention aims to provide BTK inhibitors with highselectivity for BTK inhibition over EGFR inhibition.

Furthermore, it is an aim of certain embodiments of this invention toprovide new cancer treatments. In particular, it is an aim of certainembodiments of this invention to provide compounds which have comparableactivity to existing cancer treatments, ideally they should have betteractivity. Certain embodiments of the invention also aim to provideimproved solubility compared to prior art compounds and existingtherapies. It is particularly attractive for certain compounds of theinvention to provide better activity and better solubility over knowncompounds.

It is an aim of certain embodiments of this invention to providecompounds which exhibit reduced cytotoxicity relative to prior artcompounds and existing therapies.

Another aim of certain embodiments of this invention is to providecompounds having a convenient pharmacokinetic profile and a suitableduration of action following dosing. A further aim of certainembodiments of this invention is to provide compounds in which themetabolised fragment or fragments of the drug after absorption are GRAS(Generally Regarded As Safe).

Certain embodiments of the present invention satisfy some or all of theabove aims.

SUMMARY OF THE DISCLOSURE

In accordance with the present invention there is provided compounds asdisclosed below. Furthermore, the invention provides compounds capableof inhibiting Bruton's tyrosine kinase (BTK) and the use of thesecompounds in inhibiting BTK. In accordance with the invention there isprovided a method of treating conditions modulated by BTK. The inventionprovides compounds for use in treating a condition which is modulated byBTK.

In a first aspect of the invention there is provided a compoundaccording to formula (I):

whereinA is N or CR^(a);D is either a substituted or unsubstituted C₁₋₆ alkylene chain which issaturated or unsaturated and which may also contain, where chemicallypossible, 1, 2 or 3 N, O, or S atoms in the chain which areindependently chosen at each occurrence;or wherein D represents a substituted or unsubstituted carbocyclic orheterocyclic moiety which is saturated or unsaturated and which containsfrom 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein thering is optionally substituted with —NR^(b)—, wherein —NR^(b)— is bondedto the ring; and wherein, when substituted, the alkylene chain or thecarbocyclic or heterocyclic moiety includes 1 to 5 substituentsindependently selected at each occurrence from the group comprising:halo, —OR^(b), —SR^(b), —NR^(b)R^(c), NO, ═O, —CN, acyl, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, —SO₂R^(b), and SO₃R^(b), —C(O)R^(b) andC(O)OR^(b);E is selected from: C₁₋₄ alkyl, or:

Y is either O or NR^(b);X is selected from H, methyl or CN;L¹ is selected from a bond, —O—, —O(CR^(d)R^(e))_(m)—, —NR^(b)— and—(CR^(d)R^(e))_(m)—;L² represents —NR^(b)C(O)—;n is selected from 0, 1, 2, and 3;m is selected from 1, 2, 3 and 4;o is selected from 0, 1, 2, 3 and 4;R^(a) is selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, SH,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, NR^(b)R^(c), —CN, acyl, —C(O)R^(b), —C(O)OR^(b),—SO₂R^(b), and —SO₃R^(b);R^(b) and R^(c) are independently selected at each occurrence from: H,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl;

R^(d) and R^(e) are independently selected at each occurrence from: H,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl;

R¹ is a group selected from a substituted or unsubstituted carbocyclicor heterocyclic moiety which either contains from 3 to 8 atoms in asingle ring or 7 to 14 atoms in a fused polycyclic ring system, wherein,when substituted, R¹ contains 1 to 5 substituents independently selectedat each occurrence from the group comprising: halo, —OR^(b), —SR^(b),—NR^(b)R^(c), —NO₂, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(b), SO₃R^(b), —C(O)R^(b),—C(O)OR^(b), C(O)NR^(b)R^(c) and aryl optionally substituted by 1 or 2halo atoms;

R² is selected from H, halo, —OR^(b), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl,—NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b) and —C(O)NR^(b)R^(c); and

R³, R⁴, and R⁵ are independently selected from H, halo, —OR^(b), —CN,—NR^(b)R^(c), —CH₂NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), —C(O)NR^(b)R^(c),C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl,C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl, heteroaryl, alkaryl andalkheteroaryl;or R³ and R⁴ taken together with the carbon atoms to which they areattached form a C₃₋₈ cycloalkene and R⁵ is independently selected asabove;or R⁴ and R⁵ taken together with the carbon atom to which they areattached form a C₃₋₈ cycloalkyl and R³ is independently selected asabove;or R³ and R⁵ taken together with the carbon atoms to which they areattached form a C—C triple bond and R⁴ is independently selected asabove.

In an embodiment of the invention there is provided a compound accordingto formula (I):

whereinA is N or CR^(a);D is either a substituted or unsubstituted C₁₋₆ alkylene chain which issaturated or unsaturated and which may also contain, where chemicallypossible, 1, 2 or 3 N, O, or S atoms in the chain which areindependently chosen at each occurrence;or wherein D represents a substituted or unsubstituted carbocyclic orheterocyclic moiety which is saturated or unsaturated and which containsfrom 3 to 8 atoms in the carbocyclic or heterocyclic ring, wherein thering is optionally substituted with —NR^(b)—, wherein —NR^(b)— is bondedto the ring; andwherein, when substituted, the alkylene chain or the carbocyclic orheterocyclic moiety includes 1 to 5 substituents independently selectedat each occurrence from the group comprising: halo, —OR^(b), —SR^(b),—NR^(b)R^(c), NO, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, —SO₂R^(b), and SO₃R^(b), —C(O)R^(b) and C(O)OR^(b);E is selected from: C₁₋₄ alkyl, or:

Y is either O or NR^(b);L¹ is selected from a bond, —O—, —O(CR^(d)R^(e))_(m)—, —NR^(b)— and—(CR^(d)R^(e))_(m)—;L² represents —NR^(b)C(O)—;n is selected from 0, 1, 2, and 3;m is selected from 1, 2, 3 and 4;R^(a) is selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OH, SH,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, NR^(b)R^(c), —CN, acyl, —C(O)R^(b), —C(O)OR^(b),—SO₂R^(b), and —SO₃R^(b);R^(b) and R^(c) are independently selected at each occurrence from: H,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl;R^(d) and R^(e) are independently selected at each occurrence from: H,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇halocycloalkyl;R¹ is a group selected from a substituted or unsubstituted carbocyclicor heterocyclic moiety which either contains from 3 to 8 atoms in asingle ring or 7 to 14 atoms in a fused polycyclic ring system, wherein,when substituted, R¹ contains 1 to 5 substituents independently selectedat each occurrence from the group comprising: halo, —OR^(b), —SR^(b),—NR^(b)R^(c), —NO₂, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(b), SO₃R^(b), —C(O)R^(b),—C(O)OR^(b), C(O)NR^(b)R^(c) and aryl optionally substituted by 1 or 2halo atoms;R² is selected from H, halo, —OR^(b), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl,—NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b) and —C(O)NR^(b)R^(c); andR³, R⁴, and R⁵ are independently selected from H, halo, —OR^(b), —CN,—NR^(b)R^(c), —CH₂NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), —C(O)NR^(b)R^(c),C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl,C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl, heteroaryl, alkaryl andalkheteroaryl;or R³ and R⁴ taken together with the carbon atoms to which they areattached form a C₃₋₈ cycloalkene and R⁵ is independently selected asabove;or R⁴ and R⁵ taken together with the carbon atom to which they areattached form a C₃₋₈ cycloalkyl and R³ is independently selected asabove;or R³ and R⁵ taken together with the carbon atoms to which they areattached form a C—C triple bond and R⁴ is independently selected asabove.

In embodiments, A may be an N atom. In embodiments A is CR^(a). R^(a)may be H, halo, e.g. fluoro or chloro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OH,or C₁₋₆ alkoxy. In particular R^(a) may be H, fluoro, chloro or C₁₋₄haloalkyl. In particular A may be CR^(a) and R^(a) may be H, fluoro,chloro or C₁₋₄ haloalkyl, preferably H. Hence, in an embodiment A may beCH.

Thus, the compound of formula (I) may be a compound according to formula(Ia):

L² represents —NR^(b)C(O)—. Therefore, L² can be described asrepresenting an amide, wherein the amide nitrogen is substituted byR^(b). The amide, —NR^(b)C(O)—, may be oriented in one of twodirections, as is evident to the skilled person. In other words: L² mayrepresent an amide, —NR^(b)C(O)—, wherein the nitrogen is substituted byR^(b) and the nitrogen is bonded to (CR^(d)R^(e))_(n), or the phenylring when n is 0, and the carbon is bonded to R¹ when oriented in afirst direction; or the nitrogen is bonded to R¹ and the carbon isbonded to (CR^(d)R^(e))_(n), or the phenyl ring when n is 0, whenoriented in a second direction. Thus, L² may represent —NR^(b)C(O)— or—C(O)NR^(b)—, wherein the groups are oriented in formula (I) as shown.

In all definitions of all other groups in the formulae of the inventionthe written representation of the groups is not necessarily indicativeof the only orientation of the group when the relevant group may beoriented in other chemically possible ways.

In embodiments, where n is 1, the compound of formula (I) may be acompound according to formula (Ib) or in particular formula (Ic):

Furthermore, in embodiments where n is 1, the compound of formula (I)may be a compound according to formula (Id) or in particular formula(Ie):

The groups, L¹ and (CR^(d)R^(e))_(n)-L²-R¹, on the phenyl ring ofcompounds of formula (I) and (Ia) may be substituted in any arrangementpossible. For example the groups may be in a para, ortho or metarelationship. In an embodiment, the compound of formula (I) may be acompound according to formula (IIa), having a para relationship betweenthe groups on the phenyl ring or (IIb), having a meta relationshipbetween the groups on the phenyl ring:

In embodiments where n is 1 the compound of formula (I) may be compoundsaccording to formulae (IIc) and (IId).

The group R¹ may be a substituted or unsubstituted: cycloalkyl, aryl,heterocycloalkyl or heteroaryl, wherein the cycloalkyl andheterocycloalkyl groups may be saturated or unsaturated and thecycloalkyl, aryl, heterocycloalkyl or heteroaryl may contain either from3 to 8 atoms in a single ring or 7 to 14 atoms in a fused polycyclicring system.

The group R¹ may be a substituted or unsubstituted: C₃₋₈ cycloalkyl,C₆₋₁₄ aryl, C₃₋₈ heterocycloalkyl or C₅₋₁₄ heteroaryl, wherein the C₃₋₈cycloalkyl and C₃₋₈ heterocycloalkyl groups may be saturated orunsaturated.

The group R¹ may be a substituted or unsubstituted: C₃₋₈ cycloalkyl(optionally C₃ or C₅₋₇ cycloalkyl), C₆₋₁₄ aryl (optionally C₆ C₉, or C₁₀aryl) or C₅₋₁₄ heteroaryl (optionally C₅, C₆ or C₁₀ heteroaryl), whereinthe C₃₋₈ cycloalkyl group may be saturated or unsaturated. Whensubstituted, R¹ may contain 1, 2 or 3 substituents independentlyselected at each occurrence from the group comprising: halo, —OR^(b),—SR^(b), —NR^(b)R^(c), NO, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(b), SO₃R^(b), —C(O)R^(b),—C(O)OR^(b), C(O)NR^(b)R^(c) and aryl optionally substituted by 1 or 2halo atoms.

In embodiments R¹ may be unsubstituted phenyl, unsubstituted pyridyl,substituted pyridyl or substituted phenyl.

Optionally, when R¹ is substituted it is substituted by 1, 2 or 3substituents independently selected at each occurrence from the groupcomprising: halo, —OR^(b), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, whereinR^(b) is selected from H, C₁₋₄ alkyl and C₁₋₄ haloalkyl. Preferably thesubstituents are independently selected from fluoro, chloro, methoxy,—CN, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethoxy or —OCF₃.

In embodiments R¹ may be unsubstituted phenyl or phenyl substituted with1, 2 or 3 substituents independently selected at each occurrence fromthe group comprising: halo, —OR^(b), —CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,wherein R^(b) is selected from H, C₁₋₄ alkyl and C₁₋₄ haloalkyl.Preferably the substituents are independently selected from fluoro,chloro, methoxy, —CN, methyl, ethyl, trifluoromethyl, trifluoroethyl,ethoxy or —OCF₃.

In embodiments R¹ is selected from: phenyl, fluorophenyl,difluorophenyl, chlorophenyl, methylphenyl (also referred to as tolyl),methoxyphenyl, trifluromethylphenyl, cyanophenyl,trifluoromethoxyphenyl, tert-butylphenyl, methyl-fluorophenyl (alsoreferred to as fluorotolyl), fluoro-methoxyphenyl,fluoro-trifluoromethylphenyl, fluoro-trifluoromethoxyphenyl,chloro-methoxyphenyl, methoxy-methylphenyl (also referred to asmethoxytolyl), methoxy-trifluoromethylphenyl,chloro-trifluoromethylphenyl, ethoxy-trifluoromethylphenyl,dimethoxyphenyl, di(trifluoromethyl)phenyl, trifluorophenyl andchloro-methylphenyl (also referred to as chorotolyl).

In an embodiment, R² is hydrogen.

In an embodiment, R³, R⁴, and R⁵ may be independently selected fromhydrogen, fluorine, chlorine, bromine, iodine, —CN, —CH₂NR^(b)R^(c),C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, C₁₋₆ alkylsubstituted with C₃₋₈ heterocycloalkyl, C₁₋₆ haloalkyl, aryl,heteroaryl, alkaryl and alkheteroaryl or R³ and R⁵ taken together withthe carbon atoms to which they are attached form a C—C triple bond andR⁴ is independently selected as above.

In an embodiment, R³, R⁴, and R⁵ may be independently selected fromhydrogen, fluorine, chlorine, bromine, iodine, —CN, —CH₂NR^(b)R^(c),C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, C₁₋₆ alkylsubstituted with C₃₋₈ heterocycloalkyl, C₁₋₆ haloalkyl, aryl,heteroaryl, alkaryl and alkheteroaryl.

In another embodiment, R³, R⁴, and R⁵ may be independently selected fromhydrogen, fluorine, chlorine, bromine, iodine, —CN, —CH₂NR^(b)R^(c) andC₁₋₆ alkyl or R³ and R⁵ taken together with the carbon atoms to whichthey are attached form a C—C triple bond and R⁴ is independentlyselected from hydrogen, fluorine, chlorine, bromine, iodine, —CN,—CH₂NR^(b)R^(c) and C₁₋₆ alkyl, where R^(b) and R^(c) are independentlyselected from hydrogen and C₁₋₆ alkyl.

In another embodiment, R³, R⁴, and R⁵ may be independently selected fromhydrogen, fluorine, chlorine, bromine, iodine, —CN, —CH₂NR^(b)R^(c) andC₁₋₆ alkyl, where R^(b) and R^(c) are independently selected fromhydrogen and C₁₋₆ alkyl.

In a more preferred embodiment, two of R³, R⁴, and R⁵ may be hydrogenand the other may be fluorine, chlorine, bromine, iodine, —CN,—CH₂NR^(b)R^(c) and C₁₋₆ alkyl or R³ and R⁵ taken together with thecarbon atoms to which they are attached form a C—C triple bond and R⁴ isC₁₋₆ alkyl, where R^(b) and R^(c) are independently selected fromhydrogen and C₁₋₆ alkyl. For example, R³ and R⁴ may be hydrogen; or R⁴and R⁵ may be hydrogen; or R³ and R⁵ may be hydrogen.

In a more preferred embodiment, two of R³, R⁴, and R⁵ may be hydrogenand the other may be fluorine, chlorine, bromine, iodine, —CN,—CH₂NR^(b)R^(c) and C₁₋₆ alkyl, where R^(b) and R^(c) are independentlyselected from hydrogen and C₁₋₆ alkyl. For example, R³ and R⁴ may behydrogen; or R⁴ and R⁵ may be hydrogen; or R³ and R⁵ may be hydrogen.

In a further preferred embodiment, R³, R⁴, and R⁵ are all hydrogen.

In an embodiment R³ is not —CN. Therefore, in an embodiment, R³ may beindependently selected from hydrogen, fluorine, chlorine, bromine,iodine, —CH₂NR^(b)R^(c), C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈cycloalkyl, C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₁₋₆haloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl. R⁴ and R⁵ may beas defined above.

In another embodiment, R³ may be independently selected from hydrogen,fluorine, chlorine, bromine, iodine, —CH₂NR^(b)R^(c) and C₁₋₆ alkyl,where R^(b) and R^(c) are independently selected from hydrogen and C₁₋₆alkyl. R⁴ and R⁵ may be as defined above.

In a more preferred embodiment, two of R³ may be hydrogen and the othermay be fluorine, chlorine, bromine, iodine, —CH₂NR^(b)R^(c) and C₁₋₆alkyl, where R^(b) and R^(c) are independently selected from hydrogenand C₁₋₆ alkyl. R⁴ and R⁵ may be as defined above.

In an embodiment R³, R⁴, and R⁵ are not —CN.

In an embodiment, R^(b) and R^(c) are hydrogen or C₁₋₄ alkyl, preferablyH or methyl.

In an embodiment R^(d) and R^(e) are independently selected at eachoccurrence from: H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₁₋₄ acyl.Preferably, R^(d) and R^(e) are independently selected at eachoccurrence from: H, halo (e.g. fluoro and chloro), C₁₋₄ alkyl (e.g.methyl or ethyl) or C₁₋₄ haloalkyl (e.g. trifluoromethyl ortrifluoroethyl). Further preferably R^(d) and R^(e) are H.

In embodiments n is selected from 1, 2 or 3, preferably n is 1.

In one embodiment E is:

In one embodiment E is:

In one embodiment E is C₁₋₄ alkyl or:

In one embodiment E is:

In all embodiments

wherein Y is O or NR^(b), may be selected from:

In another embodiment E is:

In all embodiments

may be selected from:

In a further embodiment E is:

In a further embodiment E is:

In a further embodiment E is:

In a further embodiment E is:

In an embodiment E is methyl or:

In embodiments Y is O. In alternative embodiments Y is NR^(a) whereinR^(a) is H or methyl.

In an embodiment o is 1 or 2.

In the statement of invention D may represent a substituted orunsubstituted carbocyclic or heterocyclic moiety which is saturated orunsaturated and which contains from 3 to 8 atoms in the carbocyclic orheterocyclic ring, wherein the ring is optionally substituted with—NR^(b)—. The group —NR^(b)— is bonded to two entities, as is evident tothe skilled person. The two entities may be the heterocyclic orcarbocyclic ring and E.

In an embodiment D is either a substituted or unsubstituted C₁₋₆alkylene chain which is saturated or unsaturated and which may alsocontain, where chemically possible, 1, 2 or 3 N, O, or S atoms in thechain which are independently chosen at each occurrence;

or wherein D represents a substituted or unsubstituted carbocyclic orheterocyclic moiety which is saturated or unsaturated and which containsfrom 3 to 8 atoms in the carbocyclic or heterocyclic ring;

and wherein, when substituted, the alkylene chain or the carbocyclic orheterocyclic moiety includes 1 to 5 substituents independently selectedat each occurrence from the group comprising: halo, —OR^(b), —SR^(b),—NR^(b)R^(c), NO, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, —SO₂R^(b), and SO₃R^(b), —C(O)R^(b) and C(O)OR^(b).

In an embodiment, D is selected from a substituted or unsubstitutedsaturated C₁₋₆ alkylene chain containing, where chemically possible, 1,2 or 3, optionally 1 or 2, N, O or S atoms in the chain which areindependently chosen at each occurrence;

or D represents a substituted or unsubstituted saturated heterocyclicmoiety which contains from 3 to 8 atoms in the heterocyclic ring andcontains, where chemically possible, 1, 2 or 3, optionally 1 or 2, N, Oor S atoms in the ring which are independently chosen at eachoccurrence.

In embodiments the alkylene chain and the heterocyclic ring contain 1heteroatom selected from N, O or S, optionally N. In embodiments thealkylene chain and the heterocyclic ring contain 1 nitrogen atom and thenitrogen atom is the point of connection with group E.

In an embodiment, D is selected from substituted or unsubstituted C₁₋₆heteroalkyl, substituted or unsubstituted C₃₋₈ heterocycloalkyl andsubstituted or unsubstituted C₃₋₈ heterocycloalkenyl. In embodiments Dmay be selected from substituted or unsubstituted C₁₋₆ heteroalkyl,substituted or unsubstituted C₃₋₈ heterocycloalkyl and substituted orunsubstituted C₃₋₈ heterocycloalkenyl where N is the heteroatom and Dcomprises 1 or 2 nitrogen atoms. In an embodiment D is substituted orunsubstituted C₃₋₈ heterocycloalkyl, optionally C₆ heterocycloalkyl. Dmay be substituted or unsubstituted piperidinyl, preferablyunsubstituted.

In an embodiment D is unsubstituted. In an alternative embodiment D issubstituted. In an embodiment D is substituted with halo, optionallyfluoro.

In an embodiment, D may be selected from:

and D may be substituted or unsubstituted. In particular, D may beunsubstituted.

In an embodiment, D may be selected from:

In an embodiment, D may be:

Optionally, D is substituted by a halo group, for example, fluoro.

In an embodiment D is cyclopentyl and E is not present.

In embodiments L¹ is selected from a bond, —(CR^(d)R^(e))_(m)—, —O— andNR^(b)—. In embodiments m is 1 or 2, optionally m is 1. In embodimentsR^(b) is independently selected from hydrogen C₁₋₆ alkyl and C₁₋₆haloalkyl and R^(d) and R^(e) are independently selected from hydrogen,fluorine, chlorine, bromine, iodine, C₁₋₆ alkyl and C₁₋₆ haloalkyl. Inembodiments R^(b), R^(d) and R^(e) are independently hydrogen or C₁₋₆alkyl.

In embodiments L¹ is selected from a bond, —CH₂—, —O— and —NH—,optionally a bond or —CH₂—.

The embodiments described above may be applied individually, or in anycombination of one another, and independently, to the compounds of theinvention, for example those compounds disclosed below.

In the case when D is:

the compound of formula (I) is a compound according to formula (III):

In any embodiment D may be the group shown below with the indicatedstereochemistry:

Thus, the compound of formula (I) may be a compound according to formula(IIIa):

In embodiments where there is a single enantiomer of the compounds ofthe invention, the compounds of the invention may have an enantiomericpurity of at least about 90% enantiomeric excess (ee), at least about95% enantiomeric excess (ee), at least about 98% enantiomeric excess(ee), at least about 99% enantiomeric excess (ee), or 100% enantiomericexcess (ee). In embodiments where there is a mixture of enantiomers ofthe compounds of the invention, the compounds of the invention may be aracemic mixture or any other mixture of enantiomers, for example thecompounds of the invention may have an enantiomeric purity of at leastabout 50% enantiomeric excess (ee), at least about 60% enantiomericexcess (ee), at least about 70% enantiomeric excess (ee), at least about80% enantiomeric excess (ee), at least about 90% enantiomeric excess(ee), or at least about 95% enantiomeric excess (ee).

In an embodiment the compound of formula (I) is a compound according toformula (IVa) and (IVb):

In an embodiment the compound of formula (I) is a compound according toformula (Va) and (Vb):

In an embodiment the compound of formula (I) is a compound according toformula (VIa) and (VIb):

In an embodiment the compound of formula (I) is a compound according toformula (VIIa) and (VIIb):

In an embodiment the compound of formula (I) is a compound according toformula (VIIIa) and (VIIIb):

Preferred compounds of the invention include:

Particularly preferred compounds of the invention are:

In another aspect of the invention there is provided a compound offormula (I) for use as a medicament.

In another aspect a compound of formula (I) is for use in the treatmentof a condition which is modulated by Bruton's tyrosine kinase (BTK).Usually conditions that are modulated by BTK are conditions that wouldbe treated by the inhibition of BTK using a compound of the presentinvention. A compound of formula (I) may be for use in the treatment ofa condition treatable by the inhibition of Bruton's tyrosine kinase(BTK).

BTK inhibition is a novel approach for treating many different humandiseases associated with the inappropriate activation of B-cells,including B-cell malignancies, immunological disease for example,autoimmune and inflammatory disorders. In embodiments the conditiontreatable by the inhibition of BTK may be selected from: cancer,lymphoma, leukemia, autoimmune diseases and inflammatory disorders.Specific conditions treatable by the inhibition of BTK may be selectedfrom: B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer, bone metastasis, arthritis, multiple sclerosisosteoporosis, irritable bowel syndrome, inflammatory bowel disease,Crohn's disease and lupus.

B-cell malignancy, B-cell lymphoma, diffuse large B cell lymphoma,chronic lymphocyte leukemia, non-Hodgkin lymphoma for example ABC-DLBCL,mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cellnon-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma,bone cancer and bone metastasis are examples of cancer, lymphoma andleukemia treatable by BTK inhibition.

Arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome,inflammatory bowel disease, Crohn's disease and lupus are examples ofimmunological diseases treatable by BTK inhibition. Arthritis is anexample of an inflammatory disorder treatable by BTK inhibition. Lupusis an example of an autoimmune disease treatable by BTK inhibition.

In embodiments, a compound of the invention may be for use in thetreatment of: cancer, lymphoma, leukemia, immunological diseases,autoimmune diseases and inflammatory disorders. The compound of theinvention may be for use in the treatment of specific conditionsselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, bone cancer, bone metastasis, arthritis, multiplesclerosis osteoporosis, irritable bowel syndrome, inflammatory boweldisease, Crohn's disease and lupus. The compounds may also be used forthe treatment of disorders associated with renal transplant.

In an embodiment the compound of the invention may be for use in thetreatment of specific conditions selected from: B-cell malignancy,B-cell lymphoma, diffuse large B cell lymphoma, chronic lymphocyteleukemia, non-Hodgkin lymphoma for example ABC-DLBCL, mantle celllymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkinlymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus andarthritis.

In an aspect of the invention there is provided a method of treatment ofa condition which is modulated by Bruton's tyrosine kinase, wherein themethod comprises administering a therapeutic amount of a compound of theinvention, to a patient in need thereof.

The method of treatment may be a method of treating a conditiontreatable by the inhibition of Bruton's tyrosine kinase.

The invention also provides a method of treating a condition selectedfrom: cancer, lymphoma, leukemia, immunological diseases autoimmunediseases and inflammatory disorders, wherein the method comprisesadministering a therapeutic amount of a compound of the invention, to apatient in need thereof. The invention also provides a method oftreating a specific condition selected from: B-cell malignancy, B-celllymphoma, diffuse large B cell lymphoma, chronic lymphocyte leukemia,non-Hodgkin lymphoma for example ABC-DLBCL, mantle cell lymphoma,follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma,Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bonemetastasis, arthritis, multiple sclerosis osteoporosis, irritable bowelsyndrome, inflammatory bowel disease, Crohn's disease and lupus, whereinthe method comprises administering a therapeutic amount of a compound offormula (I), to a patient in need thereof. The method may also treatdisorders associated with renal transplant.

In an embodiment the method may be for treating a specific conditionselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia,multiple myeloma, arthritis and lupus.

In another aspect of the invention there is provided a pharmaceuticalcomposition, wherein the composition comprises a compound of theinvention and pharmaceutically acceptable excipients.

In an embodiment the pharmaceutical composition may be a combinationproduct comprising an additional pharmaceutically active agent. Theadditional pharmaceutically active agent may be an anti-tumor agentdescribed below.

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “C₁₋₆ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl andn-hexyl. Alkylene groups may likewise be linear or branched and may havetwo places of attachment to the remainder of the molecule. Furthermore,an alkylene group may, for example, correspond to one of those alkylgroups listed in this paragraph. The alkyl and alkylene groups may beunsubstituted or substituted by one or more substituents. Possiblesubstituents are described below. Substituents for the alkyl group maybe halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C₁₋₆alkoxy.

The term “C₁₋₆ alkoxy” refers to an alkyl group which is attached to amolecule via oxygen. This includes moieties where the alkyl part may belinear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, forexample methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may bemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy,tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy groupmay be unsubstituted or substituted by one or more substituents.Possible substituents are described below. Substituents for the alkylgroup may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH,C₁₋₆ alkoxy.

The term “C₁₋₆ haloalkyl” refers to a hydrocarbon chain substituted withat least one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the hydrocarbon chain. For example, C₁₋₆haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl,chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g.1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g.1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl.

The term “C₂₋₆ alkenyl” refers to a branched or linear hydrocarbon chaincontaining at least one double bond and having 2, 3, 4, 5 or 6 carbonatoms. The double bond(s) may be present as the E or Z isomer. Thedouble bond may be at any possible position of the hydrocarbon chain.For example, the “C₂₋₆ alkenyl” may be ethenyl, propenyl, butenyl,butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

The term “C₂₋₆ alkynyl” refers to a branded or linear hydrocarbon chaincontaining at least one triple bond and having 2, 3, 4, 5 or 6 carbonatoms. The triple bond may be at any possible position of thehydrocarbon chain. For example, the “C₂₋₆ alkynyl” may be ethynyl,propynyl, butynyl, pentynyl and hexynyl.

The term “C₁₋₆ heteroalkyl” refers to a branded or linear hydrocarbonchain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least oneheteroatom selected from N, O and S positioned between any carbon in thechain or at an end of the chain. For example, the hydrocarbon chain maycontain one or two heteroatoms. The C₁₋₆ heteroalkyl may be bonded tothe rest of the molecule through a carbon or a heteroatom. For example,the “C₁₋₆ heteroalkyl” may be C₁₋₆ N-alkyl, C₁₋₆ N,N-alkyl, or C₁₋₆O-alkyl.

The term “carbocyclic” refers to a saturated or unsaturated carboncontaining ring system. A “carbocyclic” system may be monocyclic or afused polycyclic ring system, for example, bicyclic or tricyclic. A“carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example,3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Carbocyclic” encompasses cycloalkyl moieties,cycloalkenyl moieties, aryl ring systems and fused ring systemsincluding an aromatic portion.

The term “heterocyclic” refers to a saturated or unsaturated ring systemcontaining at least one heteroatom selected from N, O or S. A“heterocyclic” system may contain 1, 2, 3 or 4 heteroatoms, for example1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclicring system, for example, bicyclic or tricyclic. A “heterocyclic” moietymay contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atomsin a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.“Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenylmoieties and heteroaromatic moieties. For example, the heterocyclicgroup may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran,pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₈ cycloalkyl” refers to a saturated hydrocarbon ring systemcontaining 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the “C₃₋₈cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The term “C₃₋₈ cycloalkenyl” refers to an unsaturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.The ring may contain more than one double bond provided that the ringsystem is not aromatic. For example, the “C₃₋₈ cycloalkyl” may becyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene,cyclooctenyl and cycloatadienyl.

The term “C₃₋₈ heterocycloalkyl” refers to a saturated hydrocarbon ringsystem containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least oneheteroatom within the ring selected from N, O and S. For example theremay be 1, 2 or 3 heteroatoms, optionally 1 or 2. The “C₃₋₈heterocycloalkyl” may be bonded to the rest of the molecule through anycarbon atom or heteroatom. The “C₃₋₈ heterocycloalkyl” may have one ormore, e.g. one or two, bonds to the rest of the molecule: these bondsmay be through any of the atoms in the ring. For example, the “C₃₋₈heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane,tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine,morpholine, thiomorpholine, piperazine, and tetrahydropyran.

The term “C₃₋₈ heterocycloalkenyl” refers to an unsaturated hydrocarbonring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbonatoms and at least one heteroatom within the ring selected from N, O andS. For example there may be 1, 2 or 3 heteroatoms, optionally 1 or 2.The “C₃₋₈ heterocycloalkenyl” may be bonded to the rest of the moleculethrough any carbon atom or heteroatom. The “C₃₋₈ heterocycloalkenyl” mayhave one or more, e.g. one or two, bonds to the rest of the molecule:these bonds may be through any of the atoms in the ring. For example,the “C₃₋₈ heterocycloalkyl” may be tetrahydropyridine, dihydropyran,dihydrofuran, pyrroline.

The term “aromatic” when applied to a substituent as a whole means asingle ring or polycyclic ring system with 4n+2 electrons in aconjugated π system within the ring or ring system where all atomscontributing to the conjugated π system are in the same plane.

The term “aryl” refers to an aromatic hydrocarbon ring system. The ringsystem has 4n+2 electrons in a conjugated π system within a ring whereall atoms contributing to the conjugated π system are in the same plane.For example, the “aryl” may be phenyl and naphthyl. The aryl systemitself may be substituted with other groups.

The term “heteroaryl” refers to an aromatic hydrocarbon ring system withat least one heteroatom within a single ring or within a fused ringsystem, selected from O, N and S. The ring or ring system has 4n+2electrons in a conjugated π system where all atoms contributing to theconjugated π system are in the same plane. For example, the “heteroaryl”may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole,pyrazole, pyrazine, pyridine, pyrimidine and indole.

The term “alkaryl” refers to an aryl group, as defined above, bonded toa C₁₋₄ alkyl, where the C₁₋₄ alkyl group provides attachment to theremainder of the molecule.

The term “alkheteroaryl” refers to a heteroaryl group, as defined above,bonded to a C₁₋₄ alkyl, where the alkyl group provides attachment to theremainder of the molecule.

The term “halogen” herein includes reference to F, Cl, Br and I. Halogenmay be Cl. Halogen may be F.

When —NR^(b)— is bonded to the carbocyclic or heterocyclic ring of D,the group E is bonded directly to —NR^(b)—.

A bond terminating in a “

” represents that the bond is connected to another atom that is notshown in the structure. A bond terminating inside a cyclic structure andnot terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

Where a moiety is substituted, it may be substituted at any point on themoiety where chemically possible and consistent with atomic valencyrequirements. The moiety may be substituted by one or more substituents,e.g. 1, 2, 3 or 4 substituents; optionally there are 1 or 2 substituentson a group. Where there are two or more substituents, the substituentsmay be the same or different. The substituent(s) may be selected from:OH, NHR⁹, amidino, guanidino, hydroxyguanidino, formamidino,isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo,sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl or alkaryl. Where the group to be substituted is an alkylgroup the substituent may be ═O. Where the moiety is substituted withtwo or more substituents and two of the substituents are adjacent theadjacent substituents may form a C₄₋₈ ring along with the atoms of themoiety on which the substituents are substituted, wherein the C₄₋₈ ringis a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5,6, 7, or 8 carbon atoms and 1, 2 or 3 heteroatoms.

Substituents are only present at positions where they are chemicallypossible, the person skilled in the art being able to decide (eitherexperimentally or theoretically) without inappropriate effort whichsubstitutions are chemically possible and which are not.

Ortho, meta and para substitution are well understood terms in the art.For the absence of doubt, “ortho” substitution is a substitution patternwhere adjacent carbons possess a substituent, whether a simple group,for example the fluoro group in the example below, or other portions ofthe molecule, as indicated by the bond ending in “

”.

“Meta” substitution is a substitution pattern where two substituents areon carbons one carbon removed from each other, i.e. with a single carbonatom between the substituted carbons. In other words there is asubstituent on the second atom away from the atom with anothersubstituent. For example the groups below are meta substituted.

“Para” substitution is a substitution pattern where two substituents areon carbons two carbons removed from each other, i.e. with two carbonatoms between the substituted carbons. In other words there is asubstituent on the third atom away from the atom with anothersubstituent. For example the groups below are para substituted.

By “acyl” is meant an organic radical derived from, for example, anorganic acid by the removal of the hydroxyl group, e.g. a radical havingthe formula R—C(O)—, where R may be selected from H, C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C₁₋₃alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, acetyl, propionyl and butyryl.A particular acyl group is acetyl.

Throughout the description the disclosure of a compound also encompassespharmaceutically acceptable salts, solvates and stereoisomers thereof.Where a compound has a stereocentre, both (R) and (S) stereoisomers arecontemplated by the invention, equally mixtures of stereoisomers or aracemic mixture are completed by the present application. Where acompound of the invention has two or more stereocentres any combinationof (R) and (S) stereoisomers is contemplated. The combination of (R) and(S) stereoisomers may result in a diastereomeric mixture or a singlediastereoisomer. The compounds of the invention may be present as asingle stereoisomer or may be mixtures of stereoisomers, for exampleracemic mixtures and other enantiomeric mixtures, and diasteroemericmixtures. Where the mixture is a mixture of enantiomers the enantiomericexcess may be any of those disclosed above. Where the compound is asingle stereoisomer the compounds may still contain otherdiasteroisomers or enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) ordiastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. ofabout at least 85%

The invention contemplates pharmaceutically acceptable salts of thecompounds of formula (I). These may include the acid addition and basesalts of the compounds. These may be acid addition and base salts of thecompounds. In addition the invention contemplates solvates of thecompounds. These may be hydrates or other solvated forms of thecompound.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate,1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate andtrifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulfate and hemicalciumsalts. For a review on suitable salts, see “Handbook of PharmaceuticalSalts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may beprepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid orbase;

(ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of formula (I) or by ring-opening asuitable cyclic precursor, for example, a lactone or lactam, using thedesired acid or base; or

(iii) by converting one salt of the compound of formula (I) to anotherby reaction with an appropriate acid or base or by means of a suitableion exchange column.

All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in theresulting salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of any formula includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of a number of formulaas herein defined, including all polymorphs and crystal habits thereof,prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of the invention.

Before purification, the compounds of the present invention may exist asa mixture of enantiomers depending on the synthetic procedure used. Theenantiomers can be separated by conventional techniques known in theart. Thus the invention covers individual enantiomers as well asmixtures thereof.

For some of the steps of the process of preparation of the compounds offormula (I), it may be necessary to protect potential reactive functionsthat are not wished to react, and to cleave said protecting groups inconsequence. In such a case, any compatible protecting radical can beused. In particular methods of protection and deprotection such as thosedescribed by T. W. GREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protectinggroups, Georg Thieme Verlag, 1994), can be used. All of the abovereactions and the preparations of novel starting materials used in thepreceding methods are conventional and appropriate reagents and reactionconditions for their performance or preparation as well as proceduresfor isolating the desired products will be well-known to those skilledin the art with reference to literature precedents and the examples andpreparations hereto.

Also, the compounds of the present invention as well as intermediatesfor the preparation thereof can be purified according to variouswell-known methods, such as for example crystallization orchromatography.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma, leukemia or immunological diseases as definedhereinbefore may be applied as a sole therapy or be a combinationtherapy with an additional active agent.

The method of treatment or the compound for use in the treatment ofcancer, lymphoma or leukemia may involve, in addition to the compound ofthe invention, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof,such as alkylating agents (for example cis-platin, oxaliplatin,carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan,chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites(for example gemcitabine and antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed,cytosine arabinoside, and hydroxyurea); antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere and polokinase inhibitors); proteasome inhibitors, for examplecarfilzomib and bortezomib; interferon therapy; and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan, mitoxantrone and camptothecin);(ii) cytostatic agents such as antiestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents, for example dasatinib and bosutinib(SKI-606), and metalloproteinase inhibitors, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase;(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies,for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab,tyrosine kinase inhibitors, for example inhibitors of the epidermalgrowth factor family (for example EGFR family tyrosine kinase inhibitorssuch as gefitinib, erlotinib and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; modulators of protein regulators of cellapoptosis (for example Bcl-2 inhibitors); inhibitors of theplatelet-derived growth factor family such as imatinib and/or nilotinib(AMN107); inhibitors of serine/threonine kinases (for example Ras/Rafsignalling inhibitors such as farnesyl transferase inhibitors, forexample sorafenib, tipifarnib and lonafarnib), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitorsand cyclin dependent kinase inhibitors such as CDK2 and/or CDK4inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™);thalidomide; lenalidomide; and for example, a VEGF receptor tyrosinekinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib andpazopanib;(vi) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;(vii) immunotherapy approaches, including for example antibody therapysuch as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) andofatumumab; interferons such as interferon α; interleukins such as IL-2(aldesleukin); interleukin inhibitors for example IRAK4 inhibitors;cancer vaccines including prophylactic and treatment vaccines such asHPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T(Provenge); and toll-like receptor modulators for example TLR-7 or TLR-9agonists; and(viii) cytotoxic agents for example fludaribine (fludara), cladribine,pentostatin (Nipent™);(ix) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(x) targeted therapies, for example PI3Kd inhibitors, for exampleidelalisib and perifosine.

The method of treatment or the compound for use in the treatment ofimmunological diseases may involve, in addition to the compound of theinvention, additional active agents. The additional active agents may beone or more active agents used to treat the condition being treated bythe compound of formula (I) and additional active agent. The additionalactive agents may include one or more of the following active agents:—

(i) steroids such as corticosteroids, including glucocorticoids andmineralocorticoids, for example aclometasone, aclometasone dipropionate,aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate,betamethasone, betamethasone dipropionate, betamethasone sodiumphosphate, betamethasone valerate, budesonide, clobetasone, clobetasonebutyrate, clobetasol propionate, cloprednol, cortisone, cortisoneacetate, cortivazol, deoxycortone, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, dexamethasoneisonicotinate, difluorocortolone, fluclorolone, flumethasone,flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolonecaproate, fluocortolone pivalate, fluorometholone, fluprednidene,fluprednidene acetate, flurandrenolone, fluticasone, fluticasonepropionate, halcinonide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate,meprednisone, methylprednisolone, mometasone paramethasone, mometasonefuroate monohydrate, prednicarbate, prednisolone, prednisone,tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide,triamcinolone alcohol and their respective pharmaceutically acceptablederivatives. A combination of steroids may be used, for example acombination of two or more steroids mentioned in this paragraph;(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g.infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia),golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and5-HT_(2A) agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2,lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);(iii) anti-inflammatory drugs, for example non-steroidalanti-inflammatory drugs;(iv) dihydrofolate reductase inhibitors/antifolates, for examplemethotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim,pemetrexed, ralitrexed and pralatrexate; and(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimuspimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan,Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan)and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril,Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril,Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril,Trandolapril), phosphate-containing agents (e.g. Fosinopril),casokinins, lactokinins and lactotripeptides.

Such combination treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within a therapeutically effective dosage range describedhereinbefore and the other pharmaceutically-active agent within itsapproved dosage range.

According to a further aspect of the invention there is provided apharmaceutical product comprising a compound of formula (I), or apharmaceutically acceptable salt thereof as defined hereinbefore and anadditional active agent. The additional active agent may be ananti-tumour agent as defined hereinbefore for the combination treatmentof a condition modulated by BTK.

According to a further aspect of the invention there is provided amethod of treatment a condition modulated by BTK comprisingadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereofsimultaneously, sequentially or separately with an additional anti-tumoragent, as defined hereinbefore, to a patient in need thereof.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use simultaneously, sequentially or separately with an additionalanti-tumour agent as defined hereinbefore, in the treatment of acondition modulated by BTK.

According to another aspect of the invention there is provided a use ofthe compound of formula (I) in combination with an anti-tumor agent ashereinbefore described. The compound of formula (I) may be usedsimultaneously, sequentially or separately with the additionalanti-tumor agent The use may be in a single combination productcomprising the compound of formula (I) and the anti-tumor agent.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

According to a further aspect there is provided a method of providing acombination product, wherein the method comprises providing a compoundof formula (I) simultaneously, sequentially or separately with ananti-tumor agent, as defined hereinbefore. The method may comprisecombining the compound of formula (I) and the anti-tumor agent in asingle dosage form. Alternatively the method may comprise providing theanti-tumor agent as separate dosage forms.

The condition modulated by BTK described above may be cancer, leukemiaor cancer. More specifically the condition modulated by BTK may beselected from: B-cell malignancy, B-cell lymphoma, diffuse large B celllymphoma, chronic lymphocyte leukemia, non-Hodgkin lymphoma for exampleABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cellleukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemiaand multiple myeloma.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous. Thus, compounds ofthe invention intended for pharmaceutical use may be administered ascrystalline or amorphous products. They may be obtained, for example, assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, or spray drying, or evaporative drying.Microwave or radio frequency drying may be used for this purpose.

For the above-mentioned compounds of the invention the dosageadministered will, of course, vary with the compound employed, the modeof administration, the treatment desired and the disorder indicated. Forexample, if the compound of the invention is administered orally, thenthe daily dosage of the compound of the invention may be in the rangefrom 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligramsper kilogram body weight (mg/kg).

A compound of the invention, or pharmaceutically acceptable saltthereof, may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the compounds of theinvention, or pharmaceutically acceptable salt thereof, is inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of the compounds of theinvention, the pharmaceutical composition which is used to administerthe compounds of the invention will preferably comprise from 0.05 to 99%w (percent by weight) compounds of the invention, more preferably from0.05 to 80% w compounds of the invention, still more preferably from0.10 to 70% w compounds of the invention, and even more preferably from0.10 to 50% w compounds of the invention, all percentages by weightbeing based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe skin) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); by rectal administration in the form ofsuppositories; or by inhalation in the form of an aerosol.

For oral administration the compounds of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compounds of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules. Liquid preparations for oralapplication may be in the form of syrups or suspensions, for example,solutions containing the compound of the invention, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, sweetening agents (such as saccharine), preservativeagents and/or carboxymethylcellulose as a thickening agent or otherexcipients known to those skilled in art.

For intravenous (parenteral) administration the compounds of theinvention may be administered as a sterile aqueous or oily solution.

The size of the dose for therapeutic purposes of compounds of theinvention will naturally vary according to the nature and severity ofthe conditions, the age and sex of the animal or patient and the routeof administration, according to well-known principles of medicine.

Dosage levels, dose frequency, and treatment durations of compounds ofthe invention are expected to differ depending on the formulation andclinical indication, age, and co-morbid medical conditions of thepatient. The standard duration of treatment with compounds of theinvention is expected to vary between one and seven days for mostclinical indications. It may be necessary to extend the duration oftreatment beyond seven days in instances of recurrent infections orinfections associated with tissues or implanted materials to which thereis poor blood supply including bones/joints, respiratory tract,endocardium, and dental tissues.

EXAMPLES AND SYNTHESIS

As used herein the following terms have the meanings given: “Boc” refersto tert-butoxycarbonyl; “DCM” refers to dichloromethane; “DIPEA” refersto N,N-Diisopropylethylamine; “LCMS” refers to liquidchromatography/mass spectrometry; “MIM” refers to monoisotopic mass;“min” refers to minutes; “NMP” refers to N-methylpyrrolidinone; “TLC”refers to thin layer chromatography; “Rf” refers to Retention factor;“RT” refers to retention time; “SCX” refers to strong cation exchange;“TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran;and “TBME” refers to tert-Butyl methyl ether.

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Compoundidentity and purity confirmations were performed by LCMS UV using aWaters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detectorwavelength was 254 nM and the MS was in positive and negativeelectrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto aguard column (0.2 μm×2 mm filters) and UPLC column (C18, 50×2.1 mm, <2μm) in sequence maintained at 40° C. The samples were eluted at a flowrate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v)Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile)according to the gradients outlined in Table 1 below. Retention times RTare reported in minutes.

TABLE 1 Time (min) % A % B Long Acidic 0 95 5 1.1 95 5 6.1 5 95 7 5 957.5 95 5 8 95 5 Short Acidic 0 95 5 0.3 95 5 2 5 95 2.6 95 5 3 95 5

NMR was also used to characterise final compounds. NMR spectra wereobtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Optionally,compound Rf values on silica thin layer chromatography (TLC) plates weremeasured.

Compound purification was performed by flash column chromatography onsilica or by preparative LCMS. LCMS purification was performed using aWaters 3100 Mass detector in positive and negative electrospray mode(m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were elutedat a flow rate of 20 mL/min on a XBridge™ prep C18 5 μM OBD 19×100 mmcolumn with a mobile phase system composed of A (0.1% (v/v) Formic Acidin Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according tothe gradient outlined in Table 2 below.

TABLE 2 Time (min) % A % B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 9090 15 90 90

Chemical names in this document were generated using mol2nam—Structureto Name Conversion by OpenEye Scientific Software. Starting materialswere purchased from commercial sources or synthesised according toliterature procedures.

General Procedures

General Procedure A

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.1eq.) and the corresponding benzoic acid (1.0 eq.) in anhydrous THF (0.49M), under a nitrogen atmosphere, was added successively,N,N-diisopropylethylamine (5.0 eq.) and propylphosphonic anhydride (50%wt in EtOAc) (1.5 eq.). The reaction mixture was heated under reflux at70° C. overnight with stirring. The mixture was diluted with water andDCM, then partitioned. The aqueous layer was extracted with DCM (×2).The combined organic extracts were filtered over a phase separator andconcentrated under reduced pressure to afford the desired boronic acid.No further purification was attempted and the product was used directlyin the next step.

General Procedure B

To a suspension of 4-(aminomethyl)phenyl]boronic acid hydrochloride (1.0eq.) and DIPEA (3.0 eq.) in anhydrous THF (0.2 M) under a nitrogenatmosphere was added a solution of the corresponding benzoyl chloridederivative (1.1 eq.) in anhydrous THF (0.2 M). The reaction mixture wasstirred overnight at room temperature, quenched with a saturated aqueoussolution of ammonium chloride and then extracted into ethyl acetate(×3). The combined organics were washed with brine, dried over Na₂SO₄and filtered then concentrated under reduced pressure to afford thedesired boronic acid derivative. No further purification was attemptedand the product was used directly in the next step.

General Procedure C

A mixture of tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(1.0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassiumcarbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M) was degassedby bubbling nitrogen through it for 25 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 30 min. The mixturewas then heated at 120° C. for 14 h. The reaction mixture was filteredover Celite®. The cake was rinsed with DCM. Water was added to thefiltrate and the layers were partitioned. The aqueous layer wasextracted with DCM (2×). The combined organic extracts were filteredover phase separator and then concentrated under reduced pressure togive a dark solid. Further purification by flash column chromatography(DCM/MeOH 100:0 to 90:10) gave the desired compound.

General Procedure D

A mixture of tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(1.0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassiumcarbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M) was degassedby bubbling nitrogen through it for 15 min.1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (0.05 eq.) was added and the mixture wasdegassed again by bubbling nitrogen through it for 15 min. The mixturewas then heated under microwave irradiation at 120-140° C. for 60-90minutes. The reaction mixture was either purified by SCX and used assuch or purified using the following procedure, unless stated usedcrude. The mixture filtered over Celite®. The cake was rinsed with DCM.Water was added to the filtrate and the layers were partitioned. Theaqueous layer was extracted with DCM (2×). The combined organic extractswere filtered over phase separator and then concentrated under reducedpressure to give a dark solid. Further purification by flash columnchromatography (DCM/MeOH 100:0 to 90:10) gave the desired compound.

General Procedure E

To a solution of Boc-protected amine (1.0 eq.) in dry methanol (0.7 M)under a nitrogen atmosphere was added hydrogen chloride (20-30 eq.). Thereaction mixture was stirred at room temperature overnight, and thenconcentrated under reduced pressure to give the crude product. Furtherpurification by either SCX or flash column chromatography (dry loading,DCM/7N ammonia in MeOH 100:0 to 90:10) gave, after further drying, thedesired compound.

General Procedure F

To a suspension of amine (1.0 eq.) and acrylic acid (1.0 eq.) inanhydrous THF (0.3 M) were added successively N,N-diisopropylethylamine(3.0 eq.) and propylphosphonic anhydride (1.5 eq.). The reaction mixturewas stirred overnight at room temperature, diluted with water and DCM.The layers were partitioned. The aqueous layer was extracted with DCM(×2). The combined organic extracts were filtered over phase separatorand concentrated to give a foam. Further purification by flash columnchromatography gave the title compound.

General Procedure G

To a solution of amine (1.0 eq) in DCM (0.14 M) were added successivelywas added cyanogen bromide (4.0 eq) and triethylamine (4.0 eq). Thereaction mixture was stirred at rt for 20 min, quenched with a 1Maqueous solution of NaOH and extracted with DCM. The combined organicextracts were filtered over a phase separator, concentrated in vacuo.Further purification by flash chromatography or preparative HPLCafforded the title product.

General Procedure H

To a stirred solution of benzaldehyde (1 eq) in EtOH (0.4 M) was addedhydroxylamine hydrochloride (1.5 eq) under a nitrogen atmosphere. Thereaction mixture was stirred for 1 h and then filtered. The filtrate wasconcentrated to dryness affording the desired oxime.

General Procedure I

To a stirred solution of oxime (1 eq) and triisopropylborate (2 eq) inTHF (0.4 M) at −78° C. was added n-butyllithium solution (2.5 M, 3 eq)dropwise under nitrogen. The reaction was stirred for 90 min. Water wasadded and the mixture was brought to room temperature and concentratedin vacuo before 1 M HCl (aq) was added to bring the solution to pH 5. Awhite precipitate formed and was filtered to afford the correspondingboronic acid.

General Procedure J

To a stirred solution of imine (1 eq) and 12 M hydrochloric acid (2 eq)under nitrogen was added palladium (10 wt. % on carbon, 0.2 eq). Thereaction was placed under a hydrogen atmosphere and allowed to stir atroom temperature for 60 min. The reaction mixture was filtered throughcelite and the filtrate was concentrated to dryness. Acetone was addedand the formed precipitate was filtered to afford the correspondingamine.

Example 1:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide2-Fluoro-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide

Following general procedure A, 2-fluorobenzoic acid (182.6 mg, 1.30mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (268.7 mg,1.43 mmol) afforded crude[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid (236.8 mg, 0.87mmol, 67% yield).

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 274.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid (161.1 mg, 0.59mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(165.0 mg, 0.37 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(208.5 mg, 0.30 mmol, 82% yield) as a dark brown foam.

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 546.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(203.3 mg, 0.37 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide(118.1 mg, 0.25 mmol, 68% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.05 min, m/z 446.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide(104.0 mg, 0.22 mmol) and acrylic acid (0.02 mL, 0.22 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide(40.0 mg, 0.07 mmol, 33% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.32 min, m/z 500.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 2.98 min, m/z 500.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.96-8.93(m, 1H, NH), 8.27 (s, 1H, ArH), 7.70-7.68 (m, 1H, ArH), 7.65 (d, J 7.6Hz, 2H, ArH), 7.58-7.54 (m, 1H, ArH), 7.51 (d, J 7.6 Hz, 2H, ArH),7.34-7.28 (m, 2H, ArH), 6.87 (dd, ³J_(trans) 16.4 Hz, ³J_(cis) 10.4,0.5H), 6.72 (dd, ³J_(trans) 16.4 Hz, ³J_(cis) 10.4, 0.5H), 6.14 (d,³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d,³J_(cis) 10.4 Hz, 0.5H) 5.69 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.71 (m,1H), 4.56 (d, J 6.0 Hz, 2H), 4.55-4.51 (m, 0.5H), 4.22-4.19 (m, 1H),4.09-4.06 (m, 0.5H), 3.74-3.68 (m, 0.5H), 3.25-3.17 (m, 1H), 3.05-2.98(m, 0.5H), 2.28-2.23 (m, 1H), 2.14-2.11 (m, 1H), 1.95-1.92 (m, 1H),1.62-1.56 (m, 1H).

Example 2:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]benzamide[4-(Benzamidomethyl)phenyl]boronic acid

Following general procedure A, a mixture of[4-(aminomethyl)phenyl]boronic acid hydrochloride (262.4 mg, 1.40 mmol)and benzoic acid (155.4 mg, 1.27 mmol) gave crude[4-(benzamidomethyl)phenyl]boronic acid (201.1 mg, 0.79 mmol, 62% yield)as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 256.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-(benzamidomethyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, [4-(benzamidomethyl)phenyl]boronic acid(150.5 mg, 0.59 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(165.0 mg, 0.37 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-(benzamidomethyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(168.0 mg, 0.29 mmol, 77% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 528.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-(benzamidomethyl)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(163.7 mg, 0.31 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-benzamide(104.0 mg, 0.23 mmol, 75% yield) as a yellow/brown foam.

UPLC-MS (ES⁺, Short acidic): 1.03 min, m/z 428.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]benzamide(104 mg, 0.23 mmol) and acrylic acid (0.02 mL, 0.23 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]benzamide(31.5 mg, 0.06 mmol, 26% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.29 min, m/z 482.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 2.91 min, m/z 482.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.12 (t, J5.8 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.97-7.91 (m, 2H, ArH), 7.65 (d, J7.6 Hz, 2H, ArH), 7.57-7.47 (m, 5H, ArH), 6.87 (dd, ³J_(trans) 16.4 Hz,³J_(cis) 10.4, 0.5H) 6.71 (dd, ³J_(trans) 16.4 Hz, ³J_(cis) 10.4, 0.5H),6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.05 (d, ³J_(trans) 16.4 Hz, 0.5H),5.71 (d, ³J_(cis) 10.4 Hz, 0.5H) 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H),4.77-4.64 (m, 1H), 4.58 (d, J 6.0 Hz, 2H), 4.56-4.52 (m, 0.5H),4.25-4.16 (m, 1H), 4.12-4.03 (m, 0.5H), 3.73-3.67 (m, 0.5H), 3.24-3.16(m, 1H), 3.04-2.98 (m, 0.5H), 2.28-2.22 (m, 1H), 2.19-2.10 (m, 1H),1.98-1.92 (m, 1H), 1.66-1.55 (m, 1H).

Example 3:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide[4-[[(2,4-Difluorobenzoyl)amino]methyl]phenyl] boronic acid

Following general procedure A, 4-difluorobenzoic acid (254.2 mg, 1.61mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (331.5 mg,1.77 mmol) gave [4-[[(2,4-difluorobenzoyl)amino]methyl]phenyl]boronicacid (287.0 mg, 0.64 mmol, 40% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 291.8 [M+H]⁺

tert-Butyl(3R)-3-[4-Amino-3-[4-[[(2,4-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2,4-difluorobenzoyl)amino]methyl]phenyl]boronic acid (262.0 mg,0.54 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150.0 mg, 0.34 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2,4-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260.0 mg, 0.32 mmol, 96% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 564.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,4-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260.0 mg, 0.37 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide(123.3 mg, 0.25 mmol, 68% yield) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.08 min, m/z 464.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide(123.3 mg, 0.27 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide(33.0 mg, 0.06 mmol, 22% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.35 min, m/z 518.3 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.07 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.95 (t, J6.0 Hz, 1H, NH), 8.28 (s, 1H, ArH), 7.81-7.73 (m, 1H, ArH), 7.66 (d, J8.0 Hz, 2H, ArH), 7.51 (d, J 8.0 Hz, 2H, ArH), 7.43-7.36 (m, 1H, ArH),7.24-7.18 (m, 1H, ArH), 6.87 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz,0.5H) 6.71 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.15 (d,³J_(trans) 16.4 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d,³J_(cis) 10.4 Hz, 0.5H), 5.60 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.79-4.65 (m,1H), 4.56 (d, J 6.0 Hz, 2H), 4.56-4.49 (m, 0.5H), 4.25-4.16 (m, 1H),4.13-4.04 (m, 0.5H), 3.77-3.66 (m, 0.5H), 3.28-3.15 (m, 1H), 3.08-2.97(m, 0.5H), 2.32-2.21 (m, 1H), 2.18-2.09 (m, 1H), 1.99-1.89 (m, 1H),1.67-1.52 (m, 1H).

Example 4:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 2-methoxybenzoic acid (200 mg, 1.97 mmol)and [4-(aminomethyl)phenyl]boronic acid hydrochloride (406.5 mg, 2.17mmol) afforded [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(361.0 mg, 0.94 mmol, 48% yield) as a pale yellow solid.

UPLC-MS (ES⁺, short acidic): 1.29 min, m/z 285.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (320.9 mg, 0.84mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(250 mg, 0.56 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(168.0 mg, 0.24 mmol, 43% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 558.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(430.0 mg, 0.77 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(187.0 mg, 0.36 mmol, 48% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.08 min, m/z 458.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(187.0 mg, 0.41 mmol) and acrylic acid (0.03 mL, 0.41 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(90.0 mg, 0.16 mmol, 39% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.34 min, m/z 512.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.06 min, m/z 512.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.78 (t, J6.0 Hz, 1H, NH), 8.28 (s, 1H, ArH), 7.78 (dd, J 7.6, 1.8 Hz, 1H, ArH),7.65 (d, J 8.0 Hz, 2H, ArH), 7.52 (d, J 8.0 Hz, 2H, ArH), 7.49-7.51 (m,1H, ArH), 7.19-7.15 (m, 1H, ArH), 7.08-7.03 (m, 1H, ArH), 6.87 (dd,³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.73 (dd, ³J_(cis) 10.4,³J_(trans) 16.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d,³J_(trans) 16.4 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.60 (d,³J_(cis) 10.4 Hz, 0.5H), 4.78-4.66 (m, 1H), 4.60 (d, J 6.4 Hz, 2H),4.58-4.51 (m, 0.5H), 4.26-4.16 (m, 1H), 4.12-4.05 (m, 0.5H), 3.92 (s,3H, CH₃), 3.75-3.66 (m, 0.5H), 3.25-3.15 (m, 1H), 3.07-2.96 (m, 0.5H),2.33-2.22 (m, 1H), 2.17-2.08 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.52 (m,1H).

Example 5:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide[4-[[[2-Fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure A, 2-fluoro-5-(trifluoromethyl)benzoic acid(302.7 mg, 1.45 mmol) and [4-(aminomethyl)phenyl]boronic acidhydrochloride (406.5 mg, 2.17 mmol) afforded[4-[[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (427.0 mg, 1.06 mmol, 73% yield) as a yellow oil.

UPLC-MS (ES⁺, short acidic): 1.48 min, m/z 341.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (316.7 mg, 0.74 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(220.0 mg, 0.50 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(304.1 mg, 0.42 mmol, 85% yield) as a brown/yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.78 min, m/z 614.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(304.1 mg, 0.50 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide(140.0 mg, 0.26 mmol, 52% yield) as an off white foam.

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 514.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide(140 mg, 0.27 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide(50.0 mg, 0.08 mmol, 29% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.49 min, m/z 568.3 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.42 min, m/z 568.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.18 (t, J6.2 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.04-8.00 (m, 1H, ArH), 8.00-7.94(m, 1H, ArH), 7.67 (d, J 8.5 Hz, 2H, ArH), 7.63-7.56 (m, 1H, ArH), 7.53(d, J 8.5 Hz, 2H, ArH), 6.87 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz,0.5H) 6.72 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.13 (d,³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.71 (d,³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.77-4.65 (m,1H), 4.59 (d, J 6.0 Hz, 2H), 4.57-4.51 (m, 0.5H), 4.26-4.16 (m, 1H),4.12-4.04 (m, 0.5H), 3.76-3.67 (m, 0.5H), 3.27-3.18 (m, 1H), 3.08-2.97(m, 0.5H), 2.33-2.22 (m, 1H), 2.17-2.08 (m, 1H), 1.98-1.89 (m, 1H),1.67-1.53 (m, 1H).

Example 6:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide[4-[[(4-Fluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 4-fluorobenzoic acid (300.0 mg, 2.14mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (441.5 mg,2.36 mmol) afforded [4-[[(4-fluorobenzoyl)amino]methyl]phenyl]boronicacid (437.0 mg, 1.36 mmol, 63% yield) as a yellow oil.

UPLC-MS (ES⁺, short acidic): 1.27 min, m/z 273.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-fluorobenzoyl)amino]methyl]phenyl]boronic acid (282.7 mg, 0.83mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(230.0 mg, 0.52 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(273.6 mg, 0.42 mmol, 82% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 546.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(273.6 mg, 0.50 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide(98.0 mg, 0.21 mmol, 42% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 446.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide(98.0 mg, 0.22 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide(25.0 mg, 0.05 mmol, 22% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.33 min, m/z 500.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.01 min, m/z 500.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.14 (t, J6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 8.03-7.96 (m, 2H, ArH), 7.64 (d, J8.0 Hz, 2H, ArH), 7.50 (d, J 8.0 Hz, 2H, ArH), 7.36-7.29 (m, 2H, ArH),6.92-6.81 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H) 6.77-6.66 (dd,³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.15-6.11 (d, ³J_(trans) 16.4Hz, 0.5H), 6.09-6.04 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.18-6.01 (d,³J_(cis) 10.4 Hz, 0.5H), 5.75-5.67 (d, ³J_(cis) 10.4 Hz, 0.5H),4.78-4.64 (m, 1H), 4.57 (d, J 6.0 Hz, 2H, CH₂), 4.57-4.50 (m, 0.5H),4.24-4.14 (m, 1H), 4.12-4.03 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.26-3.14(m, 1H), 3.07-2.96 (m, 0.5H), 2.32-2.20 (m, 1H), 2.16-2.10 (m, 1H),1.97-1.89 (m, 1H), 1.66-1.51 (m, 1H).

Example 7:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide[4-[[(2,5-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, a mixture of 2,5-difluorobenzoyl chloride(0.22 mL, 1.76 mmol) and [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.60 mmol) was heated under reflux at 70° C.overnight with stirring. Further work-up afforded[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (343.6 mg,0.82 mmol, 52% yield) as a pale yellow solid.

UPLC-MS (ES⁺, short acidic): 1.30 min, m/z 291.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (350.0 mg,0.84 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(210 mg, 0.47 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(305.0 mg, 0.38 mmol, 80% yield) as a brown/yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 564.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(305.0 mg, 0.54 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(161.0 mg, 0.31 mmol, 58% yield) as an off white foam.

UPLC-MS (ES⁺, Short acidic): 1.08 min, m/z 464.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(161.0 mg, 0.35 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(75.0 mg, 0.13 mmol, 38% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.36 min, m/z 518.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.07 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.05 (t, J5.7 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.66 (d, J 7.9 Hz, 2H, ArH), 7.52(d, J 7.9 Hz, 2H, ArH), 7.51-7.47 (m, 1H, ArH), 7.43-7.38 (m, 2H, ArH),6.87 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.72 (dd, ³J_(cis)10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H),6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H),5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.56 (d, J 5.7 Hz,2H, CH₂), 4.55-4.52 (m, 0.5H), 4.25-4.16 (m, 1H), 4.12-4.04 (m, 0.5H),3.76-3.66 (m, 0.5H), 3.27-3.15 (m, 1H), 3.08-2.96 (m, 0.5H), 2.33-2.21(m, 1H), 2.18-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.68-1.52 (m, 1H).

Example 8:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide[4-[[(4-tert-Butylbenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 4-tert-butylbenzoyl chloride (0.22 mL,1.76 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300mg, 1.6 mmol) afforded[4-[[(4-tert-butylbenzoyl)amino]methyl]phenyl]boronic acid (352.2 mg,0.79 mmol, 50% yield) as a yellow/white solid.

UPLC-MS (ES⁺, short acidic): 1.59 min, m/z 311.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-tert-butylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-tert-butylbenzoyl)amino]methyl]phenyl]boronic acid (367.3 mg,0.83 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(210.0 mg, 0.47 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-tert-butylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(320.0 mg, 0.38 mmol, 81% yield) as an brown foam.

UPLC-MS (ES⁺, Short acidic): 1.87 min, m/z 584.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-tert-butylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(320.0 mg, 0.55 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide(195.0 mg, 0.38 mmol, 70% yield) as an off brown foam.

UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 484.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide(195.0 mg, 0.40 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide(49.0 mg, 0.08 mmol, 20% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.58 min, m/z 538.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.66 min, m/z 538.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.04 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.87 (d, J 7.8 Hz, 2H, ArH), 7.64(d, J 7.8 Hz, 2H, ArH), 7.53-7.46 (m, 4H, ArH), 6.87 (dd, ³J_(cis) 10.4,³J_(trans) 16.4 Hz, 0.5H), 6.72 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz,0.5H), 6.13 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4 Hz,0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz,0.5H), 4.77-4.64 (m, 1H), 4.57 (d, J 6.0 Hz, 2H, CH₂), 4.56-4.51 (m,0.5H), 4.26-4.16 (m, 1H), 4.12-4.03 (m, 0.5H), 3.75-3.66 (m, 0.5H),3.27-3.14 (m, 1H), 3.06-2.96 (m, 0.5H), 2.33-2.20 (m, 1H), 2.17-2.08 (m,1H), 1.98-1.88 (m, 1H), 1.66-1.51 (m, 1H), 1.31 (s, 9H).

Example 9:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide[4-[[(2,6-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 2,6-difluorobenzoyl chloride (0.22 mL,1.76 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0mg, 1.60 mmol) afforded[4-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]boronic acid (338.3 mg,0.81 mmol, 51% yield) as a white solid.

UPLC-MS (ES⁺, short acidic): 1.21 min, m/z 291.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]boronic acid (338.3 mg,0.82 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(205.0 mg, 0.46 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(300.0 mg, 0.43 mmol, 92% yield) as an yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 564.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(300.0 mg, 0.53 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(145.0 mg, 0.28 mmol, 53% yield) as an off white foam.

UPLC-MS (ES⁺, Short acidic): 1.01 min, m/z 464.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(145.0 mg, 0.31 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(22.0 mg, 0.04 mmol, 12% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.29 min, m/z 518.3 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 2.91 min, m/z 518.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.34 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.68 (d, J 8.0 Hz, 2H, ArH),7.60-7.52 (m, 1H, ArH), 7.51 (d, J 8.0 Hz, 2H, ArH), 7.24-7.17 (m, 2H,ArH), 6.88 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.73 (dd,³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz,0.5H), 6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz,0.5H), 5.60 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.58 (d, J6.0 Hz, 2H, CH₂), 4.56-4.51 (m, 0.5H), 4.26-4.17 (m, 1H), 4.12-4.04 (m,0.5H), 3.77-3.68 (m, 0.5H), 3.28-3.16 (m, 1H), 3.08-2.97 (m, 0.5H),2.32-2.22 (m, 1H), 2.18-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.68-1.52 (m,1H).

Example 10:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide[4-[[(4-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (363.5 mg, 1.94 mmol) and 4-fluoro-2-methoxybenzoic acid(300.0 mg, 1.76 mmol) gave[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (361.0mg, 0.89 mmol, 51% yield) as a yellow oil.

UPLC-MS (ES⁺, short acidic): 1.35 min, m/z 303.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]-phenyl]boronic acid(223.8 mg, 0.74 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(205.0 mg, 0.46 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo-[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(360.0 mg, 0.44 mmol, 95% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 576.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(360.0 mg, 0.44 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]-pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(165.0 mg, 0.31 mmol, 71% yield) as an off white foam.

UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 476.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(165.0 mg, 0.35 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(26.4 mg, 0.05 mmol, 14% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.39 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.17 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.73 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.87-7.81 (m, 1H, ArH), 7.65 (d, J8.0 Hz, 2H, ArH), 7.50 (d, J 8.0 Hz, 2H, ArH), 7.11-7.06 (m, 1H, ArH),6.91-6.86 (m, 1H, ArH), 6.88-6.82 (m, 0.5H), 6.72 (dd, ³J_(cis) 10.4,³J_(trans) 16.4 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d,³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d,³J_(cis) 10.4 Hz, 0.5H), 4.77-4.65 (m, 1H), 4.58 (d, J 6.0 Hz, 2H),4.57-4.51 (m, 0.5H), 4.26-4.16 (m, 1H), 4.13-4.04 (m, 0.5H), 3.94 (s,3H, CH₃), 3.76-3.66 (m, 0.5H), 3.26-3.15 (m, 1H), 3.06-2.97 (m, 0.5H),2.32-2.21 (m, 1H), 2.16-2.09 (m, 1H), 1.95-1.92 (m, 1H), 1.62-1.56 (m,1H).

Example 11:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide[4-[[(5-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 4-(aminomethyl)phenyl]boronic acidhydrochloride (424.1 mg, 2.26 mmol) and 5-fluoro-2-methoxy-benzoic acid(350.0 mg, 2.06 mmol) gave[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (361.0mg, 0.89 mmol, 43% yield) as a yellow oil.

UPLC-MS (ES⁺, short acidic): 1.35 min, [M+H]⁺ 303.8

tert-Butyl(3R)-3-[4-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D-2,[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]-phenyl]boronic acid(350.9 mg, 0.81 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(225.0 mg, 0.51 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(360.0 mg, 0.44 mmol, 86% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 576.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(383.0 mg, 0.47 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(195.0 mg, 0.39 mmol, 84% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.12 min, m/z 476.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(195.0 mg, 0.41 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(89.0 mg, 0.16 mmol, 39% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.40 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.17 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.87 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.65 (d, J 7.7 Hz, 2H, ArH),7.56-7.48 (m, 3H, ArH), 7.38-7.31 (m, 1H, ArH), 7.23-7.17 (m, 1H, ArH),6.87 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.73 (dd, ³J_(cis)10.4, ³J_(trans) 16.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H),6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H),5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.77-4.65 (m, 1H), 4.59 (d, J 6.0 Hz,2H, CH₂), 4.58-4.52 (m, 0.5H), 4.26-4.17 (m, 1H), 4.11-4.04 (m, 0.5H),3.91 (s, 3H, CH₃), 3.75-3.67 (m, 0.5H), 3.26-3.15 (m, 1H), 3.07-2.97 (m,0.5H), 2.34-2.21 (m, 1H), 2.17-2.08 (m, 1H), 1.98-1.88 (m, 1H),1.66-1.52 (m, 1H).

Example 12:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide[4-[[(3,5-Dimethoxybenzoyl)amino]methyl]phenyl]boronic acid

To a solution of [4-(aminomethyl)phenyl]boronic acid (200.0 mg, 1.32mmol), 3,5-dimethoxybenzoic acid (241.3 mg, 1.32 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(644.5 mg, 1.46 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine(0.35 mL, 1.99 mmol). The reaction mixture stirred at rt for 72 h, andthen extracted into ethyl acetate (10 mL). The organic layer was washedwith water twice and brine, dried over a phase separator andconcentrated in vacuo to afford[4-[[(3,5-dimethoxybenzoyl)amino]methyl]phenyl]boronic acid (410.0 mg,0.65 mmol, 49% yield) as a pale pink solid.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 315.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3,5-dimethoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3,5-dimethoxybenzoyl)amino]methyl]phenyl]boronic acid (200.0 mg,0.63 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(422.9 mg, 0.95 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3,5-dimethoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.34 mmol, 54% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.67 min, m/z 588.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide

Following general procedure E,N-[[4-[4-amino-1-[(3R)-1-(3,3-dimethylbutanoyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide(200.0 mg, 0.34 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide(120.0 mg, 0.25 mmol, 72% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.15 min, m/z 488.3 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide(100.0 mg, 0.21 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide(5.0 mg, 0.01 mmol, 5% yield)

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 542.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 542.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.09 (t, ³J6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.64 (d, ³J 8.0 Hz, 2H, ArH), 7.49(d, ³J 8.0 Hz, 2H, ArH), 7.09 (d, ⁴J 2.3 Hz, 2H, ArH), 6.86 (dd,³J_(trans) 16.1, ³J_(cis) 10.7 Hz, 0.5H), 6.71 (dd, ³J_(trans) 16.1,³J_(cis) 10.7 Hz, 0.5H), 6.66 (t, ⁴J 2.3 Hz, 1H, ArH), 6.13 (d,³J_(trans) 16.7 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.7 Hz, 0.5H), 5.71 (d,³J_(cis) 10.3 Hz, 0.5H), 5.58 (d, ³J_(cis) 10.3 Hz, 0.5H), 4.77-4.64 (m,1H, CH), 4.55 (d, ³J 6.0 Hz, 2H, CH₂), 4.55-4.50 (m, 0.5H), 4.24-4.15(m, 1H), 4.11-4.03 (m, 0.5H), 3.79 (s, 6H, CH₃), 3.74-3.65 (m, 0.5H),3.25-3.14 (m, 1H), 3.06-2.95 (m, 0.5H), 2.31-2.20 (m, 1H), 2.16-2.07 (m,1H), 1.98-1.88 (m, 1H), 1.65-1.52 (m, 1H).

Example 13:N-[[4-[4-Amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure G,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(63.8 mg, 0.14 mmol) afforded, after further purification by flashcolumn chromatography,N-[[4-[4-amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(23.0 mg, 0.05 mmol, 34% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 483.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 483.3 [M+H]⁺

¹H NMR: (400 MHz, DMSO-d₆) δ 8.79 (t, J 6.1 Hz, 1H, NH), 8.29 (s, 1H,ArH), 7.79 (dd, J 7.7, J 1.8 Hz, 1H, ArH), 7.67 (d, J 8.3 Hz, 2H, ArH),7.53 (d, J 8.3 Hz, 2H, ArH), 7.54-7.48 (m, 1H, ArH), 7.18 (d, J 8.5 Hz,1H, ArH), 7.07 (td, J 7.5, J 1.0 Hz, 1H, ArH), 4.93-4.84 (m, 1H), 4.61(d, J 6.1 Hz, 2H, CH₂), 3.93 (s, 3H, OCH₃), 3.65 (dd, J 12.5, J 4.2 Hz,1H), 3.53 (dd, J 12.5, J 10.4 Hz, 1H), 3.45-3.38 (m, 1H), 3.22-3.14 (m,1H), 2.25-2.06 (m, 2H), 1.97-1.78 (m, 2H).

Example 14:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide[4-[[(3-Chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (386.7 mg, 2.06 mmol) and 3-chloro-2-methoxy-benzoic acid(350.0 mg, 2.06 mmol) gave[4-[[(3-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (467.0mg, 0.95 mmol, 51% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 319.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (442.9mg, 0.90 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(230.0 mg, 0.52 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(327.2 mg, 0.41 mmol, 80% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 593.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(327.0 mg, 0.41 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide(173.4 mg, 0.33 mmol, 81% yield) as an orange solid.

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 492.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide(173.4 mg, 0.35 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide(20.4 mg, 0.04 mmol, 10% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 547.0 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.35 min, m/z 547.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.98 (t, ³J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.67 (d, ³J 8.0 Hz, 2H, ArH),7.63-7.59 (m, 1H, ArH), 7.57-7.52 (d, ³J 8.0 Hz, 2H, ArH), 7.54-7.50 (m,1H, ArH), 7.24 (t, ³J 7.8 Hz, 1H, ArH), 6.88 (dd, ³J_(cis) 10.4,³J_(trans) 16.4 Hz, 0.5H) 6.73 (dd, ³J_(cis) 10.4, ³J_(trans) 16.4 Hz,0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4 Hz,0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.60 (d, ³J_(cis) 10.4 Hz,0.5H), 4.78-4.66 (m, 1H, CH), 4.56 (d, ³J 6.0 Hz, 2H, CH₂), 4.57-4.50(m, 0.5H), 4.26-4.17 (m, 1H), 4.12-4.04 (m, 0.5H), 3.82 (s, 3H, OCH₃),3.76-3.67 (m, 0.5H), 3.27-3.16 (m, 1H), 3.07-2.97 (m, 0.5H), 2.33-2.22(m, 1H), 2.17-2.09 (m, 1H), 1.98-1.90 (m, 1H), 1.67-1.52 (m, 1H).

Example 15:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide[4-[[(2-Methoxy-4-methyl-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (435.1 mg, 2.32 mmol) and 4-methyl-2-methoxy-benzoic acid(350.7 mg, 2.06 mmol) gave[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]boronic acid (464.0mg, 1.16 mmol, 55% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 299.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]-boronic acid(404.0 mg, 0.95 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(240.0 mg, 0.54 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(473.0 mg, 0.49 mmol, 92% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 572.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-4-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(473.0 mg, 0.54 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide(223.5 mg, 0.45 mmol, 84% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 472.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide(223.5 mg, 0.47 mmol) afforded the title compound (19.7 mg, 0.04 mmol,8% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 526.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.28 min, m/z 526.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.70 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.73 (d, J 8.0 Hz, 1H, ArH), 7.64(d, J 8.0 Hz, 2H, ArH), 7.50 (d, J 8.0 Hz, 2H, ArH), 7.00 (s, 1H, ArH),6.91-6.84 (m, 0.5H), 6.89-6.86 (m, 1H, ArH), 6.73 (dd, ³J_(trans) 16.4,³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d,³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.60- 5.57(d, ³J_(cis) 10.4 Hz, 0.5H), 4.77-4.66 (m, 1H), 4.59 (d, J 6.0 Hz, 2H,CH₂), 4.58-4.51 (m, 0.5H), 4.27-4.16 (m, 1H), 4.13-4.04 (m, 0.5H), 3.92(s, 3H, OCH₃), 3.75-3.66 (m, 0.5H), 3.27-3.15 (m, 1H), 3.06-2.96 (m,0.5H), 2.36 (s, 3H, CH₃), 2.32-2.21 (m, 1H), 2.17-2.08 (m, 1H),1.98-1.89 (m, 1H), 1.67-1.52 (m, 1H).

Example 16:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide[4-[[(3-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (424.1 mg, 2.26 mmol) and 3-fluoro-2-methoxy-benzoic acid(350.0 mg, 2.06 mmol) gave[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (554mg, 1.10 mmol, 53% yield) as a deep red oil.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 303.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]-boronic acid(554.0 mg, 1.83 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(240 mg, 0.54 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(428.0 mg, 0.52 mmol, 96% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 576.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(428.0 mg, 0.52 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide(194.7 mg, 0.39 mmol, 75% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 476.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide(194.7 mg, 0.41 mmol) afforded the title compound (71.3 mg, 0.13 mmol,31% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.21 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.89 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.67 (d, J 8.0 Hz, 2H, ArH), 7.54(d, J 8.0 Hz, 2H, ArH), 7.45-7.38 (m, 2H, ArH), 7.24-7.16 (m, 1H, ArH),6.88 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.73 (dd, ³J_(trans)16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07(d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.60(d, ³J_(cis) 10.4 Hz, 0.5H), 4.77-4.67 (m, 1H), 4.57 (d, J 6.0 Hz, 2H,CH₂), 4.57-4.52 (m, 0.5H), 4.26-4.17 (m, 1H), 4.13-4.05 (m, 0.5H), 3.91(s, 3H, OCH₃), 3.75-3.66 (m, 0.5H), 3.26-3.16 (m, 1H), 3.06-2.97 (m,0.5H), 2.33-2.21 (m, 1H), 2.17-2.09 (m, 1H), 1.98-1.90 (m, 1H),1.66-1.53 (m, 1H).

Example 17:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide[4-[[(3-Cyanobenzoyl)amino]methyl]phenyl]boronic acid

To a solution of 3-cyanobenzoic acid (194.9 mg, 1.32 mmol),[4-(aminomethyl)phenyl]boronic acid (200.0 mg, 1.32 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(644.5 mg, 1.46 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine(0.4 mL, 1.99 mmol). The reaction mixture was then stirred under an N₂atmosphere for 24 hours, extracted into ethyl acetate (10 mL). Theorganic layer was washed with brine (3×10 mL), dried over a phaseseparator and concentrated in vacuo to afford[4-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronic acid (210.0 mg, 0.75mmol, 56% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.21 min, m/z 280.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronic acid (208.0 mg, 0.74mmol), and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(220.0 mg, 0.5 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.36 mmol, 73% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 553.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.36 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(80.0 mg, 0.17 mmol, 48% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 453.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(80.0 mg, 0.18 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(21.0 mg, 0.04 mmol, 23% yield) as a colourless gum.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 507.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.96 min, m/z 507.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.37 (t, ³J6.6 Hz, 1H, NH), 8.37 (s, 1H, ArH), 8.29-8.22 (m, 2H, ArH), 8.06-8.01(m, 1H, ArH), 7.73 (t, ³J 8.3 Hz, 1H, ArH), 7.65 (d, ³J 8.3 Hz, 2H,ArH), 7.53 (d, ³J 8.3 Hz, 2H, ArH), 7.29 (br. s, 1H, NH₂), 6.87 (dd,³J_(trans) 16.6, ³J_(cis) 10.8 Hz, 0.5H), 6.79-6.61 (m, 1.5H, NH₂+0.5H),6.14 (d, ³J_(trans) 16.6 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.6 Hz, 0.5H),5.71 (d, ³J_(cis) 10.8 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.8 Hz, 0.5H),4.78-4.64 (m, 1H, CH), 4.59 (d, ³J 6.6 Hz, 2H, CH₂), 4.57-4.51 (m,0.5H), 4.24-4.15 (m, 1H, CH), 4.12-4.03 (m, 0.5H), 3.76-3.65 (m, 0.5H),3.27-3.14 (m, 1H, CH), 3.09-2.99 (m, 0.5H), 2.32-2.22 (m, 1H), 2.17-2.08(m, 1H), 1.97-1.90 (m, 1H), 1.65-1.51 (m, 1H).

Example 18:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide[4-[[(4-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acid(200.0 mg, 1.32 mmol) and 4-methoxybenzoyl chloride (226.0 mg, 1.32mmol) afforded [4-[[(4-methoxybenzoyl)amino]methyl]phenyl]boronic acid(420.0 mg, 0.88 mmol, 66% yield) as white solid.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 285.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-methoxybenzoyl)amino]methyl]phenyl]boronic acid (211.7 mg, 0.74mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(220.0 mg, 0.50 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230.0 mg, 0.41 mmol, 83% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 558.4 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230.0 mg, 0.41 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide(120.0 mg, 0.26 mmol, 63% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 458.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide(120.0 mg, 0.26 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide(42.0 mg, 0.08 mmol, 31% yield) as a pale yellow gum.

UPLC-MS (ES⁺, Short acidic): 1.33 min, m/z 512.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.99 min, m/z 512.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.98 (t, ³J7.1 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.92 (d, ³J 8.5 Hz, 2H, ArH), 7.65(d, ³J 8.5 Hz, 2H, ArH), 7.50 (d, ³J 8.5 Hz, 2H, ArH), 7.29 (br. s, 1H,NH₂), 7.03 (d, ³J 8.5 Hz, 2H, ArH), 6.86 (dd, ³J_(trans) 16.5, ³J_(cis)10.4 Hz, 0.5H), 6.77-6.64 (br. s, 1H, NH₂), 6.72 (dd, ³J_(trans) 16.5,³J_(cis) 10.4 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.5 Hz, 0.5H), 6.07 (d,³J_(trans) 16.5 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d,³J_(cis) 10.4 Hz, 0.5H), 4.76-4.67 (m, 1H, CH), 4.60-4.55 (m, 2.5H, 0.5H& CH₂), 4.25-4.16 (m, 1H, CH), 4.11-4.03 (m, 0.5H), 3.82 (s, 3H, OCH₃),3.74-3.67 (m, 0.5H), 3.25-3.16 (m, 1H, CH), 3.05-2.98 (m, 0.5H),2.32-2.18 (m, 1H, CH), 2.16-2.10 (m, 1H, CH), 1.95-1.90 (m, 1H, CH),1.64-1.55 (m, 1H, CH).

Example 19:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide[4-[[(4-Methylbenzoyl)amino]methyl]phenyl]boronic acid

General procedure A, [4-(aminomethyl)phenyl]boronic acid (200.0 mg, 1.32mmol) and p-toluoyl chloride (0.18 mL, 1.32 mmol) gave[4-[[(4-methylbenzoyl)amino]methyl]phenyl]boronic acid (430.0 mg, 0.96mmol, 72% yield) as white solid.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 269.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-methylbenzoyl)amino]methyl]phenyl]boronic acid (218.1 mg, 0.81mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(240.0 mg, 0.54 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260.0 mg, 0.48 mmol, 88% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 542.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylategaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide(90.0 mg, 0.20 mmol, 42% yield) as a white solid.

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide(90.0 mg, 0.20 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide(78.0 mg, 0.16 mmol, 77% yield)

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 496.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.15 min, m/z 496.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.04 (t, ³J6.1 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.84 (d, ³J 7.9 Hz, 2H, ArH), 7.65(d, ³J 7.9 Hz, 2H, ArH), 7.50 (d, ³J 7.9 Hz, 2H, ArH), 7.30 (d, ³J 7.9Hz, 2H, ArH), 6.86 (dd, ³J_(trans) 16.6, ³J_(cis) 10.5 Hz, 0.5H), 6.72(dd, ³J_(trans) 16.6, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.6Hz, 0.5H), 6.07 (d, ³J_(trans) 16.6 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.5Hz, 0.5H), 5.59 (d, ³J_(cis) 10.5 Hz, 0.5H), 4.76-4.67 (m, 1H, CH), 4.56(d, ³J 6.1 Hz, 2H, CH₂), 4.56-4.50 (m, 0.5H), 4.24-4.15 (m, 1H, CH),4.11-4.03 (m, 0.5H), 3.73-3.65 (m, 0.5H), 3.26-3.16 (m, 1H, CH),3.06-2.98 (m, 0.5H), 2.36 (s, 3H, CH₃), 2.31-2.21 (m, 1H, CH), 2.15-2.09(m, 1H, CH), 1.96-1.90 (m, 1H, CH), 1.65-1.56 (m, 1H, CH).

Example 20:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamideN-[[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)-benzamide

To a solution of 3-(trifluoromethyl)benzamide (330.0 mg, 1.74 mmol) and4-bromomethylphenylboronic acid pinacol ester (431.9 mg, 1.45 mmol),cooled to 0° C. under a nitrogen atmosphere, was added sodium hydride(87.2 mg, 2.18 mmol). The reaction mixture was stirred at thistemperature for 1 h, then allowed to return to room temperature andstirred overnight. The reaction mixture was then diluted with EtOAc (20mL) and quenched with a saturated aqueous solution of NH₄Cl (20 mL) andpartitioned. The aqueous phase was extracted with EtOAc (3×10 mL). Thecombined organic extracts were washed successively with water (2×10 mL)and brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give crudeN-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide(644.0 mg, 0.79 mmol, 55% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 406.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide(642.1 mg, 0.79 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(220.0 mg, 0.50 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethyl)benzoyl]amino]-methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(559.0 mg, 0.47 mmol, 95% yield) as a brown/yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 596.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(559.0 mg, 0.47 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(80.0 mg, 0.13 mmol, 28% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 496.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(80.0 mg, 0.16 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(5.2 mg, 0.01 mmol, 6% yield) as an off-white powder.

UPLC-MS (ES⁺, short acidic): 1.50 min, m/z 550.4 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.44 min, m/z 550.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.39 (t,³J 5.4 Hz, 1H, NH), 8.29-8.22 (m, 3H, ArH), 7.97-7.92 (d, J 8.0 Hz, 1H,ArH), 7.79-7.73 (m, 1H, ArH), 7.68-7.62 (d, J 8.0 Hz, 2H, ArH),7.55-7.49 (d, J 8.0 Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.4, ³J_(cis)10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.13(d, ³J_(trans) 16.4 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.71(d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.77-4.64(m, 1H), 4.60 (d, J 6.0 Hz, 2H, CH₂), 4.59-4.51 (m, 0.5H), 4.23-4.16 (m,1H), 4.11-4.04 (m, 0.5H), 3.74-3.66 (m, 0.5H), 3.25-3.15 (m, 1H),3.05-2.99 (m, 0.5H), 2.32-2.21 (m, 1H), 2.15-2.09 (m, 1H), 1.95-1.89 (m,1H), 1.65-1.53 (m, 1H).

Example 21:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide[4-[[(4-Cyanobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 4-aminomethylphenylboronic acid (200.0mg, 1.32 mmol) and 4-cyanobenzoyl chloride (0.16 mL, 1.32 mmol) afforded[4-[[(4-cyanobenzoyl)amino]methyl]phenyl]boronic acid (400.0 mg, 0.99mmol, 75% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.21 min, m/z 280.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-cyanobenzoyl)amino]methyl]phenyl]boronic acid (189.1 mg, 0.68mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(90.0 mg, 0.16 mmol, 36% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.62 min, m/z 553.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide

Following general procedure E tert-butyl(3R)-3-[4-amino-3-[4-[[(4-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.36 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide(43.0 mg, 0.10 mmol, 26% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 453.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide(43.0 mg, 0.10 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide(10.0 mg, 0.02 mmol, 20% yield)

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 507.2 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 2.94 min, m/z 507.3 [M−H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.38 (t, ³J5.9 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.08 (d, ³J 8.6 Hz, 2H, ArH), 8.00(d, ³J 8.6 Hz, 2H, ArH), 7.65 (d, ³J 7.8 Hz, 2H, ArH), 7.51 (d, ³J 7.8Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.5, ³J_(cis) 10.6 Hz, 0.5H), 6.71(dd, ³J_(cis) 10.6 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.5 Hz, 0.5H), 6.06(d, ³J_(trans) 16.5 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.6 Hz, 0.5H), 5.59(d, ³J_(cis) 10.6 Hz, 0.5H), 4.76-4.65 (m, 1H), 4.59 (d, ³J 5.9 Hz, 2H),4.56-4.51 (m, 0.5H), 4.24-4.15 (m, 1H), 4.11-4.05 (m, 0.5H), 3.74-3.66(m, 0.5H), 3.25-3.16 (m, 1H), 3.06-2.97 (m, 0.5H), 2.32-2.22 (m, 1H),2.16-2.08 (m, 1H), 1.97-1.89 (m, 1H), 1.65-1.56 (m, 1H).

Example 22:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide[4-[[(2-Methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (434.3 mg, 2.32 mmol) and 5-fluoro-2-methoxy-benzoic acid(350.0 mg, 2.06 mmol) gave[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid (215.0mg, 0.36 mmol, 17% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 299.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]-phenyl]boronic acid(206.4 mg, 0.69 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(230.0 mg, 0.52 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(323.0 mg, 0.42 mmol, 82% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 572.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(323.0 mg, 0.42 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(147.0 mg, 0.28 mmol, 66% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 472.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(147.0 mg, 0.31 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(22.2 mg, 0.04 mmol, 13% yield) as an off-white foam.

UPLC-MS (ES⁺, short acidic): 1.45 min, m/z 526.5 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.29 min, m/z 526.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 8.75 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.65 (d, J 8.0 Hz, 2H, ArH), 7.60(d, J 2.0 Hz, 1H, ArH), 7.50 (d, J 8.0 Hz, 2H, ArH), 7.29 (ddd, J 8.4, J2.4, J 0.6 Hz, 1H, ArH), 7.06 (d, J 8.4 Hz, 1H, ArH), 6.87 (dd,³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.73 (dd, ³J_(trans) 16.4,³J_(cis) 10.4 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d,³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d,³J_(cis) 10.4 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.59 (d, J 6.0 Hz, 2H, CH₂),4.59-4.52 (m, 0.5H), 4.25-4.17 (m, 1H), 4.10-4.06 (m, 0.5H), 3.88 (s,3H, OCH₃), 3.74-3.68 (m, 0.5H), 3.25-3.17 (m, 1H), 3.04-2.98 (m, 0.5H),2.27 (s, 3H, CH₃), 2.26-2.22 (m, 1H), 2.17-2.08 (m, 1H), 1.97-1.81 (m,1H), 1.65-1.53 (m, 1H).

Example 23:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide[4-[[(4-Chlorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acid(200.0 mg, 1.32 mmol), 4-chlorobenzoyl chloride (0.20 mL, 1.32 mmol)afforded [4-[[(4-chlorobenzoyl)amino]methyl]phenyl]boronic acid (350.0mg, 0.72 mmol, 54% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 290.5 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-chlorobenzoyl)amino]methyl]phenyl]boronic acid (195.5 mg, 0.68mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(220.0 mg, 0.50 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.35 mmol, 79% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 563.0 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(253.0 mg, 0.45 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide(130.0 mg, 0.28 mmol, 62% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 462.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide(130.0 mg, 0.28 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide(12.0 mg, 0.02 mmol, 8% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 516.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.27 min, m/z 516.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.21 (t, ³J5.7 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.95 (d, ³J 8.6 Hz, 2H, ArH), 7.65(d, ³J 7.9 Hz, 2H, ArH), 7.57 (d, ³J 8.6 Hz, 2H, ArH), 7.50 (d, ³J 7.9Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.7, ³J_(cis) 10.3 Hz, 0.5H), 6.72(dd, ³J_(trans) 16.7, ³J_(cis) 10.3 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.7Hz, 0.5H), 6.07 (d, ³J_(trans) 16.7 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.3Hz, 0.5H), 5.59 (d, ³J_(cis) 10.3 Hz, 0.5H), 4.75-4.67 (m, 1H, CH), 4.57(d, ³J 5.7 Hz, 2H, CH₂), 4.55-4.50 (m, 0.5H), 4.24-4.16 (m, 1H),4.12-4.03 (m, 0.5H), 3.74-3.65 (m, 0.5H), 3.25-3.16 (m, 1H), 3.07-2.98(m, 0.5H), 2.32-2.22 (m, 1H), 2.15-2.10 (m, 1H), 1.96-1.90 (m, 1H),1.67-1.57 (m, 1H).

Example 24:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide[4-[[(4-Chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (386.7 mg, 2.06 mmol) and 4-chloro-2-methoxy-benzoic acid(350.0 mg, 1.87 mmol) gave[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (520.0mg, 1.06 mmol, 56% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 319.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]-phenyl]boronic acid(458.1 mg, 0.93 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(230 mg, 0.52 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(452.0 mg, 0.50 mmol, 96% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.79 min, m/z 593.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(4-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(452.0 mg, 0.50 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide(199.8 mg, 0.39 mmol, 78% yield) as an off-white/brown foam.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 492.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide(199.8 mg, 0.41 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide(27.7 mg, 0.05 mmol, 12% yield).

UPLC-MS (ES⁺, short acidic): 1.49 min, m/z 547.1 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.39 min, m/z 547.0 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 8.78 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.77 (d, J 8.0 Hz, 1H, ArH), 7.65(d, J 8.0 Hz, 2H, ArH), 7.51 (d, J 8.0 Hz, 2H, ArH), 7.26 (d, J 1.8 Hz,1H, ArH), 7.12 (dd, J 8.2, J 1.8 Hz, 1H, ArH), 6.87 (dd, ³J_(trans)16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz,0.5H), 4.76-4.66 (m, 1H), 4.58 (d, J 6.0 Hz, 2H, CH₂), 4.55-4.50 (m,0.5H), 4.25-4.17 (m, 1H), 4.12-4.05 (m, 0.5H), 3.95 (s, 3H, CH₃),3.75-3.67 (m, 0.5H), 3.27-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.29-2.22(m, 1H), 2.13-2.11 (m, 1H), 1.95-1.92 (m, 1H), 1.65-1.53 (m, 1H).

Example 25:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide[4-[[[2-(Trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.6 mmol) and 2-(trifluoromethoxy)benzoylchloride (395.4 mg, 1.76 mmol) gave[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid(421.3 mg, 0.87 mmol, 54% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 311.9 [M+Na]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid(427.4 mg, 1.26 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(350.0 mg, 0.40 mmol, 88% yield) as an orange solid.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 560.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(380.0 mg, 0.62 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide(200.0 mg, 0.44 mmol, 83% yield as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 512.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide(184.0 mg, 0.36 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide(22.0 mg, 0.04 mmol, 10% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 566.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.27 min, m/z 566.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) 9.07 (t, J 6.0 Hz, 1H, NH), 8.28 (s, 1H, ArH),7.68-7.63 (m, 3H, ArH), 7.63-7.59 (m, 1H, ArH), 7.55-7.44 (m, 4H, ArH),6.87 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans)16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07(d, ³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59(d, ³J_(cis) 10.4 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.55 (d, J 6.0 Hz, 2H,CH₂), 4.59-4.50 (m, 0.5H), 4.25-4.17 (m, 1H), 4.12-4.05 (m, 0.5H),3.75-3.67 (m, 0.5H), 3.29-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.33-2.22(m, 1H), 2.18-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.65-1.53 (m, 1H).

Example 26:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide[4-[[(2-Fluoro-4-methyl-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.60 mmol) and 2-fluoro-4-methylbenzoylchloride (303.8 mg, 1.76 mmol) afforded crude[4-[[(2-fluoro-4-methyl-benzoyl)amino]methyl]phenyl]boronic acid (651.5mg, 1.59 mmol, 99% yield) as an off-white solid.

UPLC-MS (ES⁺, short acidic): 1.59 min, m/z 311.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]boronic acid (368.8 mg, 1.35mmol), and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(250.0 mg, 0.45 mmol, 99% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 560.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(290.0 mg, 0.52 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide(200.0 mg, 0.44 mmol, 84% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 460.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide(200.0 mg, 0.44 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide(14.0 mg, 0.03 mmol, 6% yield).

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 514.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 514.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) 8.85-8.79 (m, 1H, NH), 8.27 (s, 1H, ArH), 7.80(t, J 7.8 Hz, 1H, ArH), 7.66 (d, J 8.0 Hz, 2H, ArH), 7.63-7.56 (m, 1H,ArH), 7.51 (d, J 8.0 Hz, 2H, ArH), 7.18-7.08 (m, 1H, ArH), 6.87 (dd,³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.4,³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d,³J_(cis) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d,³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.56 (d, J 6.0 Hz, 2H, CH₂),4.55-4.50 (m, 0.5H), 4.26-4.17 (m, 1H), 4.11-4.04 (m, 0.5H), 3.75-3.67(m, 0.5H), 3.29-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.36 (s, 3H),2.33-2.22 (m, 1H), 2.18-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.53 (m,1H).

Example 27:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide4-[[(2,4,5-Trifluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 2,4,5-trifluorobenzoyl chloride (0.13 mL,1.00 mmol) and [4-(aminomethyl)phenyl]boronic acid chloride (186.4 mg,1.00 mmol) yielded the crude product[4-[[(2,4,5-trifluorobenzoyl)amino]methyl]phenyl]boronic acid (229.1 mg,0.74 mmol, 74% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 309.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,4,5-trifluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2,4,5-trifluorobenzoyl)amino]methyl]phenyl]boronic acid (156.5 mg,0.51 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150.0 mg, 0.34 mmol), gave after further purification by flash columnchromatography (DCM/MeOH 95:5), tert-butyl(3R)-3-[4-amino-3-[4-[[(2,4,5-trifluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(153.8 mg, 0.26 mmol, 78%).

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 582.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,4,5-trifluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(153.8 mg, 0.26 mmol) gave, after purification by SCX column elutingNH₃/MeOH,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide(106.0 mg, 0.22 mmol, 83% yield).

UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 482.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide(106 mg, 0.22 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide(40 mg, 0.07 mmol, 34% yield).

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 536.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.22 min, m/z 536.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.07-9.01 (m, 1H, NH), 8.27 (s, 1H, ArH),7.83-7.68 (m, 2H, ArH), 7.66 (d, J 8.0 Hz, 2H, ArH), 7.51 (d, J 8.0 Hz,2H, ArH), 6.87 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd,³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz,0.5H), 6.07 (d, ³J_(cis) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz,0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.56 (d, J6.0 Hz, 2H, CH₂), 4.55-4.49 (m, 0.5H), 4.25-4.16 (m, 1H), 4.12-4.04 (m,0.5H), 3.75-3.67 (m, 0.5H), 3.29-3.15 (m, 1H), 3.07-2.97 (m, 0.5H),2.33-2.22 (m, 1H), 2.18-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.53 (m,1H).

Example 28:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide[4-[[[4-Fluoro-2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidchloride (186 mg, 1.00 mmol) and 4-fluoro-2-(trifluoromethyl)benzoylchloride (0.15 mL, 1.00 mmol) gave[4-[[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (304 mg, 0.89 mmol, 89% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 341.8 [M+H]⁺

Following general procedure D,[4-[[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (173 mg, 0.51 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150 mg, 0.34 mmol) afforded crude tert-butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(284 mg, 0.46 mmol, assumed quantitative) as a crude product.

UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 614.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(141 mg, 0.23 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide(91 mg, 0.18 mmol, 78% yield).

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 514.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide(91.0 mg, 0.18 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide(27.0 mg, 0.05 mmol, 27% yield).

UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 568.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.24 min, m/z 568.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.15 (t, J 6.0 Hz, 1H, NH), 8.27 (s, 1H,ArH), 7.74 (dd, J 9.4, J 2.4 Hz, 1H, ArH), 7.68-7.61 (m, 2H, ArH),7.54-7.46 (m, 3H, ArH), 7.44-7.37 (m, 1H, ArH), 6.87 (dd, ³J_(trans)16.5, ³J_(cis) 10.4 Hz, 0.5H), 6.78-6.65 (m, 0.5H), 6.13 (d, ³J_(trans)16.5 Hz, 0.5H), 6.06 (d, ³J_(cis) 16.5 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.81-4.62 (m, 1H), 4.53 (d,J 6.0 Hz, 2H, CH₂), 4.59-4.49 (m, 0.5H), 4.25-4.15 (m, 1H), 4.13-4.03(m, 0.5H), 3.76-3.67 (m, 0.5H), 3.28-3.14 (m, 1H), 3.07-2.97 (m, 0.5H),2.31-2.19 (m, 1H), 2.18-2.07 (m, 1H), 2.01-1.88 (m, 1H), 1.68-1.51 (m,1H).

Example 29:N-[[4-[4-Amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure G,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(92.0 mg, 0.20 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(21.0 mg, 0.04 mmol, 21% yield).

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 489.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.13 min, m/z 489.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) 9.10-9.01 (m, 1H, NH), 8.28 (s, 1H, ArH), 7.66(d, J 8.2 Hz, 2H, ArH), 7.52 (d, J 8.2 Hz, 2H, ArH), 7.56-7.35 (m, 3H),4.92-4.82 (m, 1H), 4.56 (d, J 6.0 Hz, 2H, CH₂), 3.64 (dd, J 12.5, 4.3Hz, 1H), 3.55 (dd, J 12.5, 10.4 Hz, 1H), 3.45-3.38 (m, 1H), 3.22-3.11(m, 1H), 2.24-2.05 (m, 2H), 1.96-1.72 (m, 2H).

Example 30:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide[4-[[[2-Methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

To a solution of 2-methoxy-3-(trifluoromethyl)benzoyl chloride (239.0mg, 1.00 mmol) in THF (2 M) under a nitrogen atmosphere at 0° C. wasadded potassium phosphate (584.0 mg, 2.75 mmol), followed by4-aminomethylphenylboronic acid hydrochloride (187.0 mg, 1.00 mmol). Thereaction was allowed to return to rt and stirred overnight. Water wasadded, and the reaction mixture extracted with EtOAc (3×). The combinedorganics extracts were dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo to afford[4-[[[2-Methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (211.0 mg, 0.60 mmol, 60% yield) as an off white solid.

UPLC-MS (ES⁺, short acidic): 1.48 min, m/z 353.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (191.0 mg, 0.54 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(160.0 mg, 0.36 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(157.0 mg, 0.25 mmol, 70% yield).

UPLC-MS (ES⁺, short acidic): 1.82 min, m/z 626.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(157.0 mg, 0.25 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide(117.0 mg, 0.22 mmol, 89% yield).

UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 526.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide(84.0 mg, 0.16 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide(44.0 mg, 0.04 mmol, 46% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 580.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.47 min, m/z 580.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.11 (t, J 6.0 Hz, 1H, NH), 8.27 (s, 1H,ArH), 7.82-7.76 (m, 2H, ArH), 7.71-7.64 (m, 2H, ArH), 7.59-7.51 (m, 2H,ArH), 7.41-7.34 (m, 1H, ArH), 6.88 (dd, ³J_(trans) 16.3, ³J_(cis) 10.4Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.3, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d,³J_(trans) 16.3 Hz, 0.5H), 6.07 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.72 (d,³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.82-4.63 (m,1H), 4.57 (d, J 6.0 Hz, 2H, CH₂), 4.60-4.50 (m, 0.5H), 4.27-4.15 (m,1H), 4.13-4.04 (m, 0.5H), 3.70 (s, 3H, CH₃), 3.76-3.65 (m, 0.5H),3.28-3.14 (m, 1H), 3.09-2.96 (m, 0.5H), 2.34-2.20 (m, 1H), 2.18-2.07 (m,1H), 1.99-1.87 (m, 1H), 1.70-1.49 (m, 1H).

Example 31:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide[4-[[[2-Fluoro-6-methoxybenzoyl]amino]methyl]phenyl]boronic acid

To a solution of 2-fluoro-6-methoxybenzoyl chloride (189.0 mg, 1.00mmol) in THF (2 M) under a nitrogen atmosphere at 0° C. was addedpotassium phosphate (584.0 mg, 2.75 mmol), followed by4-aminomethylphenylboronic acid hydrochloride (187.0 mg, 1.00 mmol). Thereaction was allowed to return to rt and stirred overnight. Water wasadded, and the reaction mixture extracted with EtOAc (3×). The combinedorganics extracts were dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo to afford[4-[[(2-fluoro-6-methoxybenzoyl)amino]methyl]phenyl]boronic acid (245.0mg, 0.81 mmol, 81% yield) as an off-white solid.

UPLC-MS (ES⁺, short acidic): 1.20 min, m/z 303.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-methoxybenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-fluoro-6-methoxybenzoyl]amino]methyl]phenyl]boronic acid (136.0mg, 0.45 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(133.0 mg, 0.30 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-methoxybenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(156.0 mg, 0.27 mmol, 90% yield).

UPLC-MS (ES⁺, short acidic): 1.60 min, m/z 576.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-methoxybenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(150.0 mg, 0.26 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide(108.0 mg, 0.23 mmol, 87% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 476.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide(76.0 mg, 0.16 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide(24.0 mg, 0.04 mmol, 27% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 530.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.93 min, m/z 530.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.00 (t, J 6.0 Hz, 1H, NH), 8.28 (s, 1H,ArH), 7.70-7.63 (m, 2H, ArH), 7.55-7.50 (m, 2H, ArH), 7.45-7.37 (m, 1H),7.03-6.66 (m, 4H), 6.14 (d, ³J_(trans) 16.5 Hz, 0.5H), 6.07 (d,³J_(trans) 16.5 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.60 (d,³J_(cis) 10.4 Hz, 0.5H), 4.79-4.64 (m, 1H), 4.54 (d, J 6.0 Hz, 2H, CH₂),4.60-4.48 (m, 0.5H), 4.27-4.16 (m, 1H), 4.14-4.04 (m, 0.5H), 3.85 (s,3H, CH₃), 3.77-3.65 (m, 0.5H), 3.29-3.14 (m, 1H), 3.09-2.95 (m, 0.5H),2.32-2.21 (m, 1H), 2.18-2.07 (m, 1H), 1.99-1.89 (m, 1H), 1.68-1.50 (m,1H).

Example 32:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide[4-[[(3-Fluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.6 mmol) and 3-fluorobenzoyl chloride (0.21mL, 1.76 mmol) afforded[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]boronic acid (438.8 mg, 1.12mmol, 70% yield) as an off white solid.

UPLC-MS (ES⁺, short acidic): 1.59 min, m/z 311.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]boronic acid (368.8 mg, 1.35mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.37 mmol, 81% yield) as yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 546.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.37 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide(187.0 mg, 0.42 mmol, 114% yield)

UPLC-MS (ES⁺, Short acidic): 1.09 min, m/z 446.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide(187.0 mg, 0.42 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide(18.0 mg, 0.04 mmol, 8% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 500.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.05 min, m/z 500.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.22 (t, J 6.0 Hz, 1H, NH), 8.27 (s, 1H,ArH), 7.79 (dt, J 7.5, J 1.2 Hz, 1H, ArH), 7.75-7.70 (m, 1H ArH), 7.65(d, J 7.8 Hz, 2H, ArH), 7.59-7.48 (m, 3H, ArH), 7.44-7.38 (m, 1H, ArH),6.91-6.82 (m, 0.5H), 6.76-6.66 (m, 0.5H), 6.13 (d, J 16.8 Hz, 0.5H),6.08 (d, J 16.8 Hz, 0.5H), 5.71 (d, J 10.4 Hz, 0.5H), 5.58 (d, J 10.4Hz, 0.5H), 4.77-4.64 (m, 1H), 4.58 (d, J 6.0 Hz, 2H, CH₂), 4.58-4.51 (m,0.5H), 4.25-4.16 (m, 1H), 4.11-4.04 (m, 0.5H), 3.75-3.66 (m, 0.5H),3.27-3.14 (m, 1H), 3.07-2.97 (m, 0.5H), 2.33-2.20 (m, 1H), 2.16-2.08 (m,1H), 1.97-1.89 (m, 1H), 1.65-1.52 (m, 1H).

Example 33:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide[4-[[[2-Methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure A, 2-methoxy-4-(trifluoromethyl)benzoic acid(300.0 mg, 1.36 mmol) and [4-(aminomethyl)phenyl]boronic acid (226.3 mg,1.50 mmol) afforded[4-[[[2-methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (360.0 mg, 0.71 mmol, 52% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 353.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(330.0 mg, 0.37 mmol, 54% yield).

UPLC-MS (ES⁺, Short acidic): 1.85 min, m/z 626.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(330.0 mg, 0.53 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide(240.0 mg, 0.46 mmol, 86% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 526.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide(240.0 mg, 0.46 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide(28.0 mg, 0.05 mmol, 11% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 580.3 [M+H]⁺

UPLC-MS (ES⁺, long acidic): 3.55 min, m/z 580.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 8.92 (t, J 6.0 Hz, 1H, NH), 8.27 (s, 1H,ArH), 7.86 (d, J 7.8 Hz, 1H, ArH), 7.80 (d, J 7.8 Hz, 2H, ArH), 7.53 (d,J 7.8 Hz, 2H, ArH), 7.44 (s, 1H, ArH), 7.40 (d, J 7.8 Hz, 1H, ArH), 6.87(dd, ³J_(trans) 16.6, ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans)16.6, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, J 16.8 Hz, 0.5H), 6.07 (d, J16.8 Hz, 0.5H), 5.71 (d, J 10.4 Hz, 0.5H), 5.58 (d, J 10.4 Hz, 0.5H),4.77-4.66 (m, 1H), 4.60 (d, J 6.0 Hz, 2H, CH₂), 4.58-4.53 (m, 0.5H),4.25-4.16 (m, 1H), 4.11-4.04 (m, 0.5H), 3.99 (s, 3H, OCH₃), 3.75-3.68(m, 0.5H), 3.27-3.14 (m, 1H), 3.06-2.97 (m, 0.5H), 2.33-2.22 (m, 1H),2.16-2.09 (m, 1H), 1.97-1.89 (m, 1H), 1.65-1.52 (m, 1H).

Example 34:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide[4-[[[2-Chloro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

To a stirred solution of 2-chloro-5-(trifluoromethyl)benzoyl chloride(0.16 mL, 1.00 mmol) in DCM (5 mL) was added triethylamine (0.56 mL,4.00 mmol) and [4-(aminomethyl)phenyl]boronic acid (151.0 mg, 1.00mmol). The resulting solution was stirred at room temperature overnight,quenched with water and then extracted with DCM. The combined organicswere filtered over phase separator and concentrated in vacuo to yield[4-[[[2-chloro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (437.8 mg, 1.22 mmol, 122% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 357.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-chloro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-chloro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (241.4 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-chloro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(126.8 mg, 0.20 mmol, 45% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 631.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-chloro-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(126.8 mg, 0.20 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide(66.4 mg, 0.13 mmol, 62% yield) as a dark yellow film.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 531.0 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide(66.4 mg, 0.13 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide(21.0 mg, 0.04 mmol, 29% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.52 min, m/z 580.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.45 min, m/z 580.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ (ppm, 1:1 mixture of conformers) 9.23 (t,³J 6.0 Hz, 1H, NH), 8.27 (d, ³J 1.6 Hz, 1H, ArH), 7.90-7.83 (m, 2H,ArH), 7.79 (d, ³J 8.3 Hz, 1H, ArH), 7.67 (d, ³J 8.0 Hz, 2H, ArH), 7.56(d, ³J 8.0 Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.0, ³J_(cis) 10.6 Hz,0.5H), 6.73 (dd, ³J_(trans) 16.0, ³J_(cis) 10.6 Hz, 0.5H), 6.14 (d,³J_(trans) 16.0 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.0 Hz, 0.5H), 5.72 (d,³J_(cis) 10.6 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.6 Hz, 0.5H), 4.78-4.66 (m,1H), 4.58 (d, ³J 6.0 Hz, 2H, CH₂), 4.58-4.52 (m, 1H), 4.25-4.17 (m,0.5H), 4.12-4.05 (m, 0.5H), 3.76-3.67 (m, 0.5H), 3.28-3.18 (m, 1H),3.07-2.98 (m, 0.5H), 2.33-2.21 (m, 1H), 2.17-2.09 (m, 1H), 1.98-1.90 (m,1H), 1.67-1.55 (m, 1H).

Example 35:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide[4-[[(3-Chlorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.60 mmol) and 3-chlorobenzoyl chloride (0.23mL, 1.76 mmol) gave [4-[[(3-chlorobenzoyl)amino]methyl]phenyl]boronicacid (519.9 mg, 1.17 mmol, 73% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.38 min, m/z 289.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-chlorobenzoyl)amino]methyl]phenyl]boronic acid (146.6 mg, 0.51mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150.0 mg, 0.36 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(153.0 mg, 0.27 mmol, 81% yield) as a brown foam.

LC-MS (ES⁺, Short acidic): 1.74 min, m/z 563.0 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(153.0 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide(74.0 mg, 0.16 mmol, 59% yield) as a yellow oil.

LC-MS (ES⁺, Short acidic): 1.18 min, m/z 462.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide(74.0 mg, 0.16 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide(36.0 mg, 0.07 mmol, 43% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 517.0 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.25 min, m/z 516.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers)

9.24 (t, ³J 6.0 Hz, 1H, ArH), 8.27 (s, 1H, ArH), 7.97 (t, ³J 1.8 Hz, 1H,ArH), 7.91-7.88 (m, 1H, ArH), 7.66-7.62 (m, 3H, ArH), 7.57-7.49 (m, 3H,ArH), 6.87 (dd, ³J_(trans) 16.8, ³J_(cis) 10.5 Hz, 0.5H), 6.72 (dd,³J_(trans) 16.8, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.8 Hz,0.5H), 6.07 (d, ³J_(trans) 16.8 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.5 Hz,0.5H), 5.59 (d, ³J_(cis) 10.5 Hz, 0.5H), 4.78-4.66 (m, 1H, CH), 4.57 (d,³J 6.0 Hz, 2H, CH₂), 4.58-4.51 (m, 0.5H), 4.25-4.16 (m, 1H, CH),4.11-4.04 (m, 0.5H), 3.75-3.66 (m, 0.5H), 3.27-3.17 (m, 1H), 3.07-2.97(m, 0.5H), 2.33-2.21 (m, 1H), 2.17-2.08 (m, 1H), 1.97-1.90 (m, 1H),1.66-1.52 (m, 1H).

Example 36:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide[4-[[[2-Fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

To 2-fluoro-4-(trifluoromethyl)benzoyl chloride (226 mg, 1 mmol) under anitrogen atmosphere at 0° C. was added potassium phosphate (584 mg; 2.75mmol.), followed by 4-aminomethylphenylboronic acid hydrochloride (187mg, 1.00 mmol). The reaction was allowed to return to rt and stirredovernight. Water was added, and the reaction mixture extracted withEtOAc (3 times). The combined organics extracts were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo to afford[4-[[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (245 mg, 0.72 mmol, 72% yield) as yellow oil, which was used crudein the next step.

UPLC-MS (ES⁺, short acidic): 1.42 min, m/z 341.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (144 mg, 0.42 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(125 mg, 0.28 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(111 mg, 0.18 mmol, 64% yield).

UPLC-MS (ES⁺, short acidic): 1.83 min, m/z 614.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(111 mg, 0.18 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide(76 mg, 0.15 mmol, 82% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 514.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide(73 mg, 0.14 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide(64 mg, 0.11 mmol, 79% yield) as a white solid

UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 568.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.47 min, m/z 568.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.19 (t, ³J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.91-7.82 (m, 2H, ArH), 7.73-7.63(m, 3H, ArH), 7.53 (d, ³J 8.3 Hz, 2H, ArH), 6.88 (dd, ³J_(trans) 16.2,³J_(cis) 10.5 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz,0.5H), 6.14 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.2 Hz,0.5H), 5.72 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.5 Hz,0.5), 4.78-4.65 (m, 1H), 4.59 (d, ³J 6.0 Hz, 2H, CH₂), 4.58-4.50 (m,0.5H), 4.26-4.16 (m, 1H), 4.12-4.04 (m, 0.5H), 3.75-3.67 (m, 0.5H),3.30-3.15 (m, 1H), 3.08-2.98 (m, 0.5H), 2.32-2.21 (m, 1H), 2.18-2.08 (m,1H), 1.98-1.89 (m, 1H), 1.66-1.53 (m, 1H).

Example 37:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide[4-[[(3-Fluoropyridine-4-carbonyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acid(294.2 mg, 1.95 mmol) and 2-fluoronicotinic acid (250.0 mg, 1.77 mmol)afforded [4-[[(3-fluoropyridine-4-carbonyl)amino]methyl]phenyl]boronicacid (160.0 mg, 0.58 mmol, 33% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.03 min, m/z 274.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-4-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-fluoropyridine-4-carbonyl)amino]methyl]phenyl]boronic acid(166.6 mg, 0.61 mmol), tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-4-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(160.0 mg, 0.20 mmol, 51% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.50 min, m/z 547.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-4-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(160.0 mg, 0.29 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide(100.0 mg, 0.22 mmol, 77% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 0.97 min, m/z 447.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide(100.0 mg, 0.22 mmol) afforded, after purification by preparative HPLCand salt removal by SCX cartridge,N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide(7.0 mg, 0.01 mmol, 5% yield).

UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 501.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.65 min, m/z 501.3 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.26 (t,³J 6.0 Hz, 1H, NH), 8.72 (d, ³J 1.6 Hz, 1H, ArH), 8.56 (dd, ³J 5.0, ⁴J1.3 Hz, 1H, ArH), 8.27 (s, 1H, ArH), 7.67-7.63 (m, 3H, ArH), 7.52 (d, ³J8.5 Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz, 0.5H),6.71 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans)16.2 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.2 Hz, 0.5H), 5.71 (d, ³J_(cis)10.5 Hz, 0.5H), 5.58 (d, ³J_(cis) 10.5 Hz, 0.5H), 4.77-4.64 (m, 1H),4.58 (d, ³J 6.0 Hz, 2H, CH₂), 4.56-4.51 (m, 0.5H), 4.24-4.16 (m, 1H),4.11-4.04 (m, 0.5H), 3.75-3.67 (m, 0.5H), 3.25-3.15 (m, 1H), 3.07-2.98(m, 0.5H), 2.32-2.21 (m, 1H), 2.16-2.09 (m, 1H), 1.98-1.89 (m, 1H),1.66-1.53 (m, 1H).

Example 38:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide[4-[[(3-Fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acid(294.2 mg, 1.95 mmol) and 3-fluoropyridine-2-carboxylic acid (250.0 mg,1.77 mmol) afforded[4-[[(3-fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid(190.0 mg, 0.69 mmol, 39% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 0.94 min, m/z 274.7 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[[4-[[(3-fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid(185.1 mg, 0.68 mmol), tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230.0 mg, 0.42 mmol, 93% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.55 min, m/z 547.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230.0 mg, 0.42 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide(110.0 mg, 0.25 mmol, 59% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 447.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide(100.0 mg, 0.22 mmol) afforded, after purification by preparative HPLCand salt removal by SCX cartridge,N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide(13.0 mg, 0.03 mmol, 11% yield) as a thin film.

UPLC-MS (ES⁺, Short acidic): 1.24 min, m/z 501.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.75 min, m/z 501.3 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.30 (t,³J 6.4 Hz, 1H, NH), 8.51 (dt, J 4.6, J 1.5 Hz, 1H, ArH), 8.26 (s, 1H,ArH), 7.91-7.86 (m, 1H, ArH), 7.71-7.67 (m, 1H, ArH), 7.64 (d, ³J 8.0Hz, 2H, ArH), 7.51 (d, ³J 8.3 Hz, 2H, ArH), 6.86 (dd, ³J_(trans) 16.2,³J_(cis) 10.5 Hz, 0.5H), 6.71 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz,0.5H), 6.12 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.2 Hz,0.5H), 5.71 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.58 (d, ³J_(cis) 10.5 Hz,0.5H), 4.77-4.64 (m, 1H), 4.56 (d, ³J 6.0 Hz, 2H, CH₂), 4.55-4.51 (m,0.5H), 4.25-4.16 (m, 1H), 4.11-4.03 (m, 0.5H), 3.74-3.65 (m, 0.5H),3.26-3.15 (m, 1H), 3.04-2.96 (m, 0.5H), 2.31-2.22 (m, 1H), 2.16-2.07 (m,1H), 1.97-1.89 (m, 1H), 1.66-1.52 (m, 1H).

Example 39:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide[4-[[(2-Fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

To a solution of 2-fluoro-3-methoxy-benzoyl chloride (0.29 mL, 1.66mmol) in THF (2 M) under a nitrogen atmosphere at 0° C. was addedpotassium phosphate tribasic (878.8 mg, 4.14 mmol), followed by[4-(aminomethyl)phenyl]boronic acid (250.0 mg, 1.66 mmol). The reactionwas allowed to return to rt and stirred overnight. Water was added, andthe reaction mixture extracted with EtOAc (3×). The combined organicsextracts were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to afford crude[4-[[(2-fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (200.0mg, 0.67 mmol, 40% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 303.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (204.7mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.35 mmol, 77% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 576.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-3-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.35 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide(130.0 mg, 0.27 mmol, 78% yield) as a pale foam.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 476.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide(130.0 mg, 0.27 mmol) afforded, after purification by preparative HPLCand salt removal by SCX cartridge,N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide(16.0 mg, 0.03 mmol, 11% yield) as a thin film.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 530.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.03 min, m/z 530.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 8.95 (t,³J 6.1 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.65 (d, ³J 7.6 Hz, 2H, ArH),7.50 (d, ³J 7.6 Hz, 2H, ArH), 7.32-7.26 (m, 1H, ArH), 7.23-7.18 (m, 1H,ArH), 7.17-7.13 (m, 1H, ArH), 6.86 (dd, ³J_(trans) 16.5, ³J_(cis) 10.5Hz, 0.5H), 6.71 (dd, ³J_(trans) 16.5, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d,³J_(trans) 16.5 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.5 Hz, 0.5H), 5.70 (d,³J_(cis) 10.5 Hz, 0.5H), 5.58 (d, ³J_(cis) 10.5 Hz, 0.5H), 4.76-4.64 (m,1H), 4.55 (d, ³J 6.0 Hz, 2H, CH₂), 4.57- 4.50 (m, 0.5H), 4.25-4.15 (m,1H), 4.11-4.06 (m, 0.5H), 3.87 (s, 3H, OCH₃), 3.74-3.66 (m, 0.5H),3.27-3.15 (m, 1H), 3.04-2.96 (m, 0.5H), 2.32-2.21 (m, 1H), 2.16-2.07 (m,1H), 1.99-1.88 (m, 1H), 1.65-1.53 (m, 1H).

Example 40:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide[4-[[(2-Chlorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.6 mmol) and 2-chlorobenzoyl chloride (308.1mg, 1.76 mmol) gave [4-[[(2-chlorobenzoyl)amino]methyl]phenyl]boronicacid (368.2 mg, 0.95 mmol, 60% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 289.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[2-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-chlorobenzoyl)amino]methyl]phenyl]boronic acid (367.5 mg, 0.95mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(235 mg, 0.53 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-chlorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(450 mg, 0.52 mmol, 98% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.65 min, m/z 563.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-chlorobenzoyl)amino]-methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(450.0 mg, 0.52 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide(192 mg, 0.37 mmol, 72% yield) as an off-white/brown foam.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 462.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl]methyl]-2-chloro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide(192.0 mg, 0.42 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide(22.4 mg, 0.04 mmol, 10% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 517.1 [M+H]⁺ (96%)

UPLC-MS (ES⁺, Long acidic): 2.99 min, m/z 517 [M+H]⁺ (97%)

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.06 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.66 (d, J 8.0 Hz, 2H, ArH), 7.55(d, J 8.0 Hz, 2H, ArH), 7.53-7.48 (m, 2H, ArH), 7.48-7.40 (m, 2H, ArH),6.88 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.73 (dd, ³J_(trans)16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07(d, ³J_(trans) 16.4 Hz, 0.5H), 5.72 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59(d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.55 (d, J 6.0 Hz, 2H,CH₂), 4.57-4.50 (m, 0.5H), 4.27-4.17 (m, 1H), 4.13-4.04 (m, 0.5H),3.76-3.67 (m, 0.5H), 3.27-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.31-2.22(m, 1H), 2.18-2.09 (m, 1H), 1.98-1.90 (m, 1H), 1.67-1.52 (m, 1H).

Example 41:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide[4-[[(3-Methylbenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 3-methylbenzoylchloride (0.2 mL, 1.76mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300.0 mg,1.60 mmol) afforded [4-[[(3-methylbenzoyl)amino]methyl]phenyl]boronicacid (393.8 mg, 0.97 mmol, 60% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.33 min, m/z 269.8 [M] (66%)

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D-2,[4-[[(3-methylbenzoyl)amino]methyl]phenyl]boronic acid (181.7 mg, 0.68mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 90:10) to give tert-butyl(3R)-3-[4-amino-3-[4-[[(3-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(161.0 mg, 0.24 mmol, 53% yield) as a dark brown gum

UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 542.5 [M+H]⁺ (82%)

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(161.0 mg, 0.30 mmol) gave, after further purification by flash columnchromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide(100.8 mg, 0.21 mmol, 69% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.15 min, m/z 442.3 [M+H]⁺ (98%)

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide(100.8 mg, 0.23 mmol) gave, purification by flash column chromatography(DCM/MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide(34.7 mg, 0.06 mmol, 28% yield) as a cream solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 496.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 496.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.06 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.77-7.74 (m, 1H, ArH), 7.73-7.70(m, 1H, ArH), 7.67-7.62 (m, 2H, ArH), 7.52-7.48 (m, 2H, ArH), 7.40-7.35(m, 2H, ArH), 6.87 (dd, ³J_(trans) 16.2, ³J_(cis) 10.4 Hz, 0.5H), 6.72(dd, ³J_(trans) 16.2, ³J_(cis) 10.4 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.2Hz, 0.5H), 6.07 (d, ³J_(trans) 16.2 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.65 (m, 1H), 4.56 (d,J 6.0 Hz, 2H, CH₂), 4.57-4.51 (m, 0.5H), 4.25-4.16 (m, 1H), 4.12-4.04(m, 0.5H), 3.76-3.66 (m, 0.5H), 3.26-3.15 (m, 1H), 3.07-2.97 (m, 0.5H),2.38 (s, 3H, CH₃), 2.31-2.21 (m, 1H), 2.17-2.09 (m, 1H), 1.98-1.89 (m,1H), 1.67-1.52 (m, 1H).

Example 42:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide[4-[[[4-(Trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid

Following general procedure B, 4-(trifluoromethoxy)benzoyl chloride (0.3mL, 1.76 mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride(300.0 mg, 1.60 mmol) gave[4-[[[4-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid(547.9 mg, 1.21 mmol, 76% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 339.8 [M+H]⁺

tert-Butyl(3R)-3-[4-Amino-3-[4-[[[4-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid(229.0 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 90:10), tert-butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(161.0 mg, 0.21 mmol, 47% yield) as a yellow-brown solid

UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 612.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(133.4 mg, 0.22 mmol) gave, after further purification by flash columnchromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide(76.0 mg, 0.13 mmol, 61% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 512.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide(76.0 mg, 0.15 mmol) gave, purification by flash column chromatography(DCM/MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide(39.7 mg, 0.06 mmol, 43% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1.53 min, m/z 566.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.48 min, m/z 566.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.24 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.07-8.03 (m, 2H, ArH), 7.68 (d, J7.7 Hz, 2H, ArH), 7.53-7.48 (m, 4H, ArH), 6.87 (dd, ³J_(trans) 16.2,³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.2, ³J_(cis) 10.4 Hz,0.5H), 6.13 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.2 Hz,0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz,0.5H), 4.78-4.65 (m, 1H), 4.58 (d, J 6.0 Hz, 2H, CH₂), 4.57-4.51 (m,0.5H), 4.25-4.16 (m, 1H), 4.12-4.04 (m, 0.5H), 3.75-3.66 (m, 0.5H),3.26-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.31-2.21 (m, 1H), 2.17-2.09 (m,1H), 1.98-1.89 (m, 1H), 1.67-1.52 (m, 1H).

Example 43:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide[4-[[[2-Methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300.0 mg, 1.6 mmol) and2-methoxy-5-(trifluoromethyl)benzoyl chloride (0.35 mL, 1.76 mmol) gave[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 353.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (238.4 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(354.8 mg, 0.57 mmol, 126% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.82 min, m/z 626.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(354.8 mg, 0.57 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide(191.0 mg, 0.36 mmol, 64% yield) as a pale yellow film.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 526.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide(191.0 mg, 0.36 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide(88.4 mg, 0.15 mmol, 42% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 580.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.51 min, m/z 580.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.92 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.05 (d, J 2.2 Hz, 1H, ArH), 7.87(dd, J 8.7, J 2.2 Hz, 1H, ArH), 7.66 (d, J 7.9 Hz, 2H, ArH), 7.52 (d, J7.9 Hz, 2H, ArH), 7.38 (d, J 8.7 Hz, 1H, ArH), 6.87 (dd, ³J_(trans)16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5Hz, 0.5H), 6.14 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.2Hz, 0.5H), 5.71 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.5 Hz,0.5H), 4.78-4.65 (m, 1H), 4.58 (d, J 6.0 Hz, 2H, CH₂), 4.57-4.52 (m,0.5H), 4.25-4.17 (m, 1H), 4.12-4.04 (m, 0.5H), 4.00 (s, 3H, OCH₃),3.75-3.67 (m, 0.5H), 3.27-3.15 (m, 1H), 3.07-2.98 (m, 0.5H), 2.31-2.21(m, 1H), 2.17-2.09 (m, 1H), 1.98-1.89 (m, 1H), 1.67-1.52 (m, 1H).

Example 44:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide[4-[[[2-Fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.6 mmol) and 2-Fluoro-3-(trifluoromethyl)benzoylchloride (398.5 mg, 1.76 mmol) gave[4-[[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (484.9 mg, 1.07 mmol, 67% yield) as an off-white gum.

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 341.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]-phenyl]boronicacid (484 mg, 1.42 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(240 mg, 0.54 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo-[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(501 mg, 0.53 mmol, 98% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.80 min, m/z 614.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(501 mg, 0.53 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide(195.6 mg, 0.36 mmol, 68% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.24 min, m/z 514.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-methyl]-2-fluoro-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide(195.6 mg, 0.38 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide(44.2 mg, 0.07 mmol, 19% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.50 min, m/z 568.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.40 min, m/z 568.4 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.22 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.00-7.90 (m, 2H, ArH), 7.67 (d, ³J8.0 Hz, 2H, ArH), 7.57-7.49 (m, 3H, ArH), 6.87 (dd, ³J_(trans) 16.4,³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz,0.5H), 6.14 (d, ³J_(trans) 16.4 Hz, 0.5H), 6.07 (d, ³J_(trans) 16.4 Hz,0.5H), 5.71 (d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz,0.5H), 4.78-4.66 (m, 1H), 4.58 (d, J 6.0 Hz, 2H, CH₂), 4.56-4.50 (m,0.5H), 4.26-4.16 (m, 1H), 4.12-4.06 (m, 0.5H), 3.77-3.66 (m, 0.5H),3.28-3.15 (m, 1H), 3.08-2.97 (m, 0.5H), 2.31-2.21 (m, 1H), 2.18-2.08 (m,1H), 1.98-1.89 (m, 1H), 1.68-1.51 (m, 1H).

Example 45:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide[4-[[(5-Chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (386.7 mg, 2.06 mmol) and 5-chloro-2-methoxybenzoic acid(350.0 mg, 1.88 mmol) gave[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (259.0mg, 0.53 mmol, 28% yield as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 319.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]-boronic acid(458.1 mg, 0.93 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(230.0 mg, 0.52 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(452.0 mg, 0.50 mmol, 96% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.79 min, m/z 593.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(5-chloro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(452.0 mg, 0.50 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide(103.0 mg, 0.16 mmol, 32% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 492.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-methyl]-5-chloro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]-pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide(103.0 mg, 0.21 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide(15.0 mg, 0.03 mmol, 12% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 547.0 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.37 min, m/z 547.0 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.86 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.71 (d, J 2.8 Hz, 1H, ArH), 7.65(d, J 8.0 Hz, 2H, ArH), 7.56-7.48 (m, 3H, ArH), 7.21 (d, J 9.2 Hz 1H,ArH), 6.87 (dd, ³J_(trans) 16.4 ³J_(cis) 10.4 Hz, 0.5H), 6.72 (dd,³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.14 (d, ³J_(trans) 16.4 Hz,0.5H), 6.07 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.4 Hz,0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.64 (m, 1H), 4.58 (d, J6.0 Hz, 2H, CH₂), 4.56-4.51 (m, 0.5H), 4.26-4.16 (m, 1H), 4.12-4.04 (m,0.5H), 3.92 (s, 3H, OCH₃), 3.76-3.66 (m, 0.5H), 3.27-3.14 (m, 1H),3.06-2.97 (m, 0.5H), 2.31-2.21 (m, 1H), 2.18-2.09 (m, 1H), 1.98-1.88 (m,1H), 1.68-1.51 (m, 1H).

Example 46:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide[4-[[[3-(Trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 3-(trifluoromethoxy)benzoylchloride (395.4 mg, 1.76 mmol) gave[4-[[[3-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronic acid(565.3 mg, 1.25 mmol, 78% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 339.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[3-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]-boronic acid(448.9 mg, 0.99 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(245 mg, 0.55 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(452.0 mg, 0.48 mmol, 87% yield) as a brown foam.

LC-MS (ES⁺, Short acidic): 2.35 min, m/z 612.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[3-(trifluoromethoxy)-benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(580 mg, 0.62 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide(192.0 mg, 0.36 mmol, 58% yield) as an off-white/brown foam.

LC-MS (ES⁺, Short acidic): 1.30 min, m/z 512.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-methyl]-3-(trifluoromethoxy)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]-pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide(173 mg, 0.34 mmol) and acrylic acid (0.02 mL, 0.34 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide(42.8 mg, 0.07 mmol, 21% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 566.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.49 min, m/z 566.3 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.30 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.98 (d, J 7.6 Hz, 1H, ArH),7.90-7.86 (m, 1H, ArH), 7.70-7.62 (m, 3H, ArH), 7.58 (d, J 8.0 Hz, 1H,ArH), 7.51 (d, J 8.0 Hz, 2H, ArH), 6.87 (dd, ³J_(trans) 16.4, ³J_(cis)10.4 Hz, 0.5H), 6.72 (dd, ³J_(trans) 16.4, ³J_(cis) 10.4 Hz, 0.5H), 6.13(d, ³J_(trans) 16.4 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.4 Hz, 0.5H), 5.71(d, ³J_(cis) 10.4 Hz, 0.5H), 5.59 (d, ³J_(cis) 10.4 Hz, 0.5H), 4.78-4.64(m, 1H), 4.59 (d, J 6.0 Hz, 2H, CH₂), 4.56-4.50 (m, 0.5H), 4.26-4.16 (m,1H), 4.12-4.03 (m, 0.5H), 3.76-3.67 (m, 0.5H), 3.27-3.14 (m, 1H),3.08-2.97 (m, 0.5H), 2.31-2.21 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.89 (m,1H), 1.69-1.51 (m, 1H).

Example 47:N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide[3-[[(5-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 5-fluoro-2-methoxybenzoic acid (200.0 mg,1.18 mmol) and [3-(aminomethyl)phenyl]boronic acid (195.2 mg, 1.29 mmol)afforded [3-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (250.0 mg, 0.82 mmol, 70% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 303.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[3-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (204.6mg, 0.68 mmol), and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(250.0 mg, 0.43 mmol, 96% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.75 min, m/z 576.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(250.0 mg, 0.43 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(90.0 mg, 0.18 mmol, 43% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 476.4 [M+H]⁺

N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(90.0 mg, 0.19 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide(26.0 mg, 0.02 mmol, 26% yield) as a colourless gum.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 530.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 530.4 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 8.91 (t,³J 7.6 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.66 (br. s, 1H, ArH), 7.57-7.44(m, 4H, ArH), 7.35-7.30 (m, 1H, ArH), 7.19-7.15 (m, 1H, ArH), 6.86 (dd,³J_(trans) 16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.73 (dd, ³J_(trans) 16.2,³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.07 (d,³J_(trans) 16.2 Hz, 0.5H), 5.70 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.59 (d,³J_(cis) 10.5 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.59 (d, ³J 6.0 Hz, 2H,CH₂), 4.58-4.51 (m, 0.5H), 4.29-4.17 (m, 1H), 4.12-4.04 (m, 0.5H), 3.87(s, 3H, OCH₃), 3.72-3.64 (m, 0.5H), 3.25-3.15 (m, 1H), 3.02-2.92 (m,0.5H), 2.32-2.22 (m, 1H), 2.16-2.08 (m, 1H), 1.96-1.88 (m, 1H),1.65-1.51 (m, 1H).

Example 48:N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide[3-[[(4-Fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 4-fluoro-2-methoxybenzoic acid (200.0 mg,1.18 mmol) and [3-(aminomethyl)phenyl]boronic acid (195.2 mg, 1.29 mmol)gave [3-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid(250.0 mg, 0.82 mmol, 70% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 303.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[3-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (204.7mg, 0.68 mmol), and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200.0 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(204.0 mg, 0.35 mmol, 78% yield).

UPLC-MS (ES⁺, Short acidic): 1.76 min, m/z 576.4 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(204.0 mg, 0.35 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(150 mg, 0.32 mmol, 89% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.19 min, m/z 476.3 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(150.0 mg, 0.32 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide(33.0 mg, 0.06 mmol, 20% yield) as a colourless gum.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 530.3 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 8.76 (t,³J 6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.83 (dd, J 8.6, J 7.2 Hz, 1H,ArH), 7.64 (br. s, 1H, ArH), 7.56-7.43 (m, 3H, ArH), 7.07-7.04 (m, 1H,ArH), 6.88-6.83 (m, 1H, ArH), 6.89-6.80 (m, 0.5H), 6.72 (dd, ³J_(trans)16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.07(d, ³J_(trans) 16.2 Hz, 0.5H), 5.70 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.59(d, ³J_(cis) 10.5 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.58 (d, ³J 6.0 Hz, 2H,CH₂), 4.58-4.52 (m, 0.5H), 4.28-4.17 (m, 1H), 4.11-4.03 (m, 0.5H), 3.89(s, 3H, OCH₃), 3.73-3.64 (m, 0.5H), 3.25-3.17 (m, 1H), 3.00-2.92 (m,0.5H), 2.32-2.22 (m, 1H), 2.15-2.08 (m, 1H), 1.96-1.87 (m, 1H),1.63-1.53 (m, 1H).

Example 49:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide[4-[[[3,5-Bis-trifluoromethylbenzoyl]amino]methyl]phenyl]boronic acid

To a solution of 3,5-bis(trifluoromethyl)benzoyl chloride (276 mg, 1.00mmol) in THF (2 mL) under a nitrogen atmosphere at 0° C. was addedpotassium phosphate (584.0 mg, 2.75 mmol), followed by4-aminomethylphenylboronic acid hydrochloride (187 mg, 1.00 mmol). Thereaction was allowed to return to rt and stirred overnight. Water wasadded, and the reaction mixture extracted with EtOAc (3×). The combinedorganics extracts were dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo to afford[4-[[[(3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid(378 mg, 0.97 mmol, 97% yield) as an off-white solid.

UPLC-MS (ES⁺, short acidic): 1.68 min, m/z 392.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, (using[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) as thecatalyst),[4-[[[3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid(234 mg, 0.6 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(177.7 mg, 0.40 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(125 mg, 0.19 mmol, 47% yield).

UPLC-MS (ES⁺, short acidic): 1.98 min, m/z 664.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[3,5-bis(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(176 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide(151 mg, 0.27 mmol, 100% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.48 min, m/z 564.1 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide(151 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide(11 mg, 0.02 mmol, 6% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 618.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.92 min, m/z 618.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ (ppm, 1:1 mixture of conformers): 9.60 (t,³J 6.0 Hz, 1H, NH), 8.59 (s, 2H, ArH), 8.36 (s, 1H, ArH), 8.27 (s, 1H,ArH), 7.66 (d, J 7.9 Hz, 2H, ArH), 7.54 (d, J 7.9 Hz, 2H, ArH), 6.87(dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.71 (dd, ³J_(trans)16.2, ³J_(cis) 10.5 Hz, 0.5H), 6.13 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.06(d, ³J_(trans) 16.2 Hz, 0.5H), 5.71 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.58(d, ³J_(cis) 10.5 Hz, 0.5H), 4.76-4.66 (m, 1H), 4.63 (d, ³J 6.0 Hz, 2H,CH₂), 4.58-4.51 (m, 0.5H), 4.24-4.15 (m, 1H), 4.12-4.03 (m, 0.5H),3.76-3.66 (m, 0.5H), 3.25-3.17 (m, 1H), 3.08-2.99 (m, 0.5H), 2.33-2.20(m, 1H), 2.15-2.08 (m, 1H), 1.99-1.88 (m, 1H), 1.65-1.53 (m, 1H).

Example 50:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide[4-[[[2-Methoxy-6-methylbenzoyl]amino]methyl]phenyl]boronic acid

2-Methoxy-6-methylbenzoic acid (166 mg, 1.00 mmol) was refluxed inthionyl chloride (1 mL) for 3 h. The cooled mixture was concentratedunder reduced pressure, and traces of thionyl chloride were removed byco-evaporating (twice) with DCM under reduced pressure. To the residueunder a nitrogen atmosphere at 0° C. was added potassium phosphate(584.0 mg; 2.75 mmol), followed by 4-aminomethylphenylboronic acidhydrochloride (187 mg, 1.00 mmol). The reaction was allowed to return tort and stirred overnight. Water was added, and the reaction mixtureextracted with EtOAc (3×). The combined organics extracts were driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo toafford [4-[[[2-methoxy-6-methylbenzoyl]amino]methyl]phenyl]boronic acid(267 mg, 0.89 mmol, 89% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 299.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-6-methylbenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-methoxy-6-methylbenzoyl]amino]methyl]phenyl]boronic acid (252mg, 0.84 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(250 mg, 0.56 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-6-methylbenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(216 mg, 0.38 mmol, 67% yield).

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 572.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-methoxy-6-methylbenzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(216 mg, 0.38 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide(172 mg, 0.36 mmol, 96% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 0.99 min, m/z 472.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide

Following general procedure F (but with two further additions of theco-reagents to ensure complete conversion),N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide(151 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide(24 mg, 0.05 mmol, 22% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 526.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.05 min, m/z 526.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): δ (ppm, 1:1 mixture of conformers): 8.77 (t,³J 6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.66 (d, J 7.9 Hz, 2H, ArH), 7.55(d, J 7.9 Hz, 2H, ArH), 7.25 (t, J 7.9 Hz, 1H, ArH), 6.93-6.80 (m, 2H,ArH), 6.90-6.79 (m, 0.5H), 6.74 (dd, ³J_(trans) 16.2, ³J_(cis) 10.5 Hz,0.5H), 6.14 (d, ³J_(trans) 16.2 Hz, 0.5H), 6.08 (d, ³J_(trans) 16.2 Hz,0.5H), 5.72 (d, ³J_(cis) 10.5 Hz, 0.5H), 5.60 (d, ³J_(cis) 10.5 Hz,0.5H), 4.77-4.66 (m, 1H), 4.60-4.50 (m, 0.5H), 4.53 (d, ³J 6.0 Hz, 2H,CH₂), 4.27-4.15 (m, 1H), 4.13-4.04 (m, 0.5H), 3.79 (s, 3H, OCH₃),3.76-3.68 (m, 0.5H), 3.29-3.17 (m, 1H), 3.08-2.97 (m, 0.5H), 2.34-2.22(m, 1H), 2.21 (s, 3H, CH₃), 2.17-2.09 (m, 1H), 1.99-1.88 (m, 1H),1.66-1.52 (m, 1H).

Example 51:N-[[4-[4-Amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxybenzamide

Following general procedure G,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxybenzamide(59 mg, 0.12 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxybenzamide(41 mg, 0.08 mmol, 66%).

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 501.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.28 min, m/z 501.4 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) 8.87 (t, J 6.1 Hz, 1H, NH), 8.28 (s,1H, ArH), 7.65 (d, J 8.2 Hz, 2H, ArH), 7.53 (dd, J 9.1, J 3.3 Hz, 1H,ArH), 7.51 (d, J 8.2 Hz, 2H, ArH), 7.38-7.32 (m, 1H, ArH), 7.20 (dd, J9.1, J 4.3 Hz, 1H, ArH), 4.91-4.83 (m, 1H), 4.59 (d, J 6.1 Hz, 2H, CH₂),3.91 (s, 3H, CH₃), 3.64 (dd, ²J 12.4, ³J 4.2 Hz, 1H), 3.53 (dd, ²J 12.4,³J 10.3 Hz, 1H), 3.44-3.36 (m, 1H), 3.21-3.12 (m, 1H), 2.24-2.05 (m,2H), 1.96-1.74 (m, 2H).

Example 52:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide[4-[[[4-(Trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid

To a solution of 4-(aminomethyl)phenyl]boronic acid (250.0 mg, 1.66mmol) in water (2 mL) was added 50% aqueous potassium hydroxide (1 mL),followed by 4-(trifluoromethyl)benzoyl chloride (0.3 mL, 1.99 mmol). Thereaction mixture was stirred for 16 h, acidified with 1 M HCl. Thefiltrate was then washed with water to afford[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid (300.0mg, 0.93 mmol, 56% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.47 min, m/z 323.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid (305.4mg, 0.95 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(280.0 mg, 0.63 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.34 mmol, 53% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.77 min, m/z 596.5 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[4-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(200.0 mg, 0.34 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide(140.0 mg, 0.28 mmol, 84% yield) as an off white solid.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 496.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide(140.0 mg, 0.28 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide(11.0 mg, 0.015 mmol, 5% yield).

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 550.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers): 9.36 (t,³J 7.1 Hz, 1H, NH), 8.27 (s, 1H, ArH), 8.12 (d, ³J 8.9 Hz, 2H, ArH),7.89 (d, ³J 8.9 Hz, 2H, ArH), 7.65 (d, ³J 8.9 Hz, 2H, ArH), 7.52 (d, ³J8.9 Hz, 2H, ArH), 6.86 (dd, ³J_(trans) 16.0, ³J_(cis) 10.6 Hz, 0.5H),6.72 (dd, ³J_(trans) 16.0, ³J_(cis) 10.6 Hz, 0.5H), 6.13 (d, ³J_(trans)16.0 Hz, 0.5H), 6.06 (d, ³J_(trans) 16.0 Hz, 0.5H), 5.71 (d, ³J_(cis)10.6 Hz, 0.5H), 5.58 (d, ³J_(cis) 10.6 Hz, 0.5H), 4.76-4.67 (m, 1H, CH),4.60 (d, 2H, ³J 7.1 Hz, CH₂), 4.58-4.43 (m, 0.5H, 0.5×CH), 4.23-4.18 (m,1H), 4.10-4.06 (m, 0.5H), 3.74-3.68 (m, 0.5H), 3.25-3.16 (m, 1H),3.06-2.99 (m, 0.5H), 2.31-2.22 (m, 1H), 2.16-2.10 (m, 1H), 1.96-1.91 (m,1H), 1.66-1.55 (m, 1H).

Example 53:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide[4-[[(2,3-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 2,3-difluorobenzoyl chloride (0.22mL, 1.76 mmol) afforded crude[4-[[(2,3-difluorobenzoyl)amino]methyl]phenyl]boronic acid (445 mg, 0.99mmol, 62% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.29 min, m/z 292.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,3-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) and2,3-difluoro-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(252 mg, 0.68 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2,3-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230 mg, 0.41 mmol, 91% yield) as an orange solid.

UPLC-MS (ES⁺, Short acidic): 1.68 min, m/z 564.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,3-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(230 mg, 0.41 mmol) gave the title compound (160 mg, 0.35 mmol, 85%yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 464.2 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide(160 mg, 0.35 mmol) and acrylic acid (24 μL, 0.35 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide(50 mg, 0.09 mmol, 25% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 518.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.13 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.12 (t, J6.0 Hz, 1H, NH), 8.32 (s, 1H, ArH), 7.69-7.63 (m, 2H, ArH), 7.63-7.54(m, 1H), 7.52 (d, J 8.1 Hz, 2H, ArH), 7.49-7.43 (m, 1H, ArH), 7.35-7.27(m, 1H, ArH), 6.93-6.63 (m, 1H), 6.19-6.01 (m, 1H), 5.75-5.53 (m, 1H),4.82-4.65 (m, 1H), 4.57 (d, J 6.0 Hz, 2H), 4.61-4.50 (m, 1H), 4.25-4.14(m, 1H), 4.12-4.02 (m, 0.5H), 3.78-3.64 (m, 0.5H), 3.29-3.14 (m, 1H),3.09-2.97 (m, 0.5H), 2.29-2.20 (m, 1H), 2.18-2.07 (m, 1H), 1.99-1.88 (m,1H), 1.69-1.50 (m, 1H).

Example 54:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide[4-[[(3,5-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 4-(aminomethyl)phenylboronic acidhydrochloride (187 mg, 1.00 mmol) and 3,5-difluorobenzoyl chloride (0.12mL, 1.00 mmol) gave[4-[[(3,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (171 mg, 0.59mmol, 59% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 293.2 [M+2]+

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (172 mg, 0.59mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(175 mg, 0.39 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[4-[[(3,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(190 mg, 0.34 mmol, 86% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 464.2 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(190 mg, 0.34 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide(132 mg, 0.29 mmol, 85% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 564.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide(83 mg, 0.18 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide(28 mg, 0.05 mmol, 30% yield).

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.28 (t, J5.9 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.69-7.58 (m, 4H, ArH), 7.54-7.44(m, 3H, ArH), 6.93-6.63 (m, 1H), 6.17-6.00 (m, 1H), 5.74-5.54 (m, 1H),4.78-4.62 (m, 1H), 4.57 (d, J 5.9 Hz, 2H), 4.55-4.51 (m, 1H), 4.26-4.14(m, 1H), 4.12-4.01 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.25-3.14 (m, 1H),3.07-2.96 (m, 0.5H), 2.31-2.18 (m, 1H), 2.17-2.08 (m, 1H), 2.00-1.89 (m,1H), 1.68-1.49 (m, 1H).

Example 55:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide[4-[[(2-Fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 4-aminomethylphenylboronic acidhydrochloride (303 mg, 1.62 mmol) and 2-fluoro-5-methoxybenzoic acid(250 mg, 1.47 mmol) gave[4-[[(2-fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (334mg, 1.10 mmol, 75% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 303.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (205mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(305 mg, 0.53 mmol, assumed quantitative) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 576.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(305 mg, 0.53 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide(230 mg, 0.48 mmol, 91% yield) as a light brown foam.

UPLC-MS (ES⁺, Short acidic): 1.13 min, m/z 476.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide(230 mg, 0.48 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide(37 mg, 0.07 mmol, 15% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.40 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.95-8.88(m, 1H, NH), 8.26 (s, 1H, ArH), 7.68-7.61 (m, 2H, ArH), 7.54-7.48 (m,2H, ArH), 7.25 (dd, J 10.2, 8.9 Hz, 1H, ArH), 7.17 (dd, J 5.5, 3.2 Hz,1H, ArH), 7.11-7.05 (m, 1H, ArH), 6.92-6.635 (m, 1H), 6.18-6.01 (m, 1H),5.75-5.55 (m, 1H), 4.78-4.63 (m, 1H), 4.58-4.51 (m, 0.5H), 4.55 (d, J5.9 Hz, 2H), 4.26-4.14 (m, 1H), 4.13-4.02 (m, 1H), 3.78 (s, 3H),3.74-3.65 (m, 0.5H), 3.26-3.14 (m, 1H), 3.07-2.96 (m, 0.5H), 2.32-2.20(m, 1H), 2.16-2.07 (m, 1H), 1.97-1.87 (m, 1H), 1.66-1.51 (m, 1H).

Example 56:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide[4-[[[2-Fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, 2-fluoro-6-(trifluoromethyl)benzoylchloride (0.17 mL, 1.10 mmol) and 4-aminomethylphenylboronic acidhydrochloride (207 mg, 1.10 mmol) afforded crude[4-[[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (467 mg, 1.10 mmol, assumed quantitative) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.34 min, m/z 341.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (230 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(251 mg, 0.41 mmol, 91% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 614.5 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(251 mg, 0.41 mmol) gave crudeN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide(229 mg, 0.41 mmol, assumed quantitative) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 514.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide(229 mg, 0.41 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide(51 mg, 0.09 mmol, 20% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 568.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.20 min, m/z 568.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.33 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.75-7.62 (m, 5H, ArH), 7.54-7.48(m, 2H, ArH), 6.93-6.66 (m, 1H), 6.18-6.01 (m, 1H), 5.75-5.55 (m, 1H),4.79-4.64 (m, 1H), 4.57 (d, J 6.0 Hz, 2H), 4.56-4.50 (m, 0.5H),4.26-4.16 (m, 1H), 4.12-4.03 (m, 0.5H), 3.77-3.66 (m, 0.5H), 3.28-3.15(m, 1H), 3.08-2.95 (m, 0.5H), 2.31-2.21 (m, 1H), 2.18-2.06 (m, 1H),1.98-1.88 (m, 1H), 1.67-1.51 (m, 1H).

Example 57:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide[4-[[[4-Fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, 4-fluoro-3-(trifluoromethyl)benzoylchloride (227 mg, 1.00 mmol) and 4-aminomethylphenylboronic acidhydrochloride (187 mg, 1.00 mmol) gave[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (245 mg, 0.72 mmol, 72% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 341.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (230 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(194 mg, 0.32 mmol, 70% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 614.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(194 mg, 0.32 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide(155 mg, 0.30 mmol, 95% yield) as a pale yellow film.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 514.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide(155 mg, 0.30 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide(19 mg, 0.03 mmol, 11% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 568.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.54 min, m/z 568.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.38 (t, J6.0 Hz, 1H, NH), 8.36-8.28 (m, 2H, ArH), 8.26 (s, 1H, ArH), 7.71-7.61(m, 3H, ArH), 7.54-7.48 (m, 2H, ArH), 6.92-6.63 (m, 1H), 6.17-6.00 (m,1H), 5.74-5.54 (m, 1H), 4.79-4.63 (m, 1H), 4.59 (d, J 6.0 Hz, 2H),4.58-4.50 (m, 1H), 4.25-4.14 (m, 1H), 4.12-4.02 (m, 0.5H), 3.75-3.65 (m,0.5H), 3.25-3.15 (m, 1H), 3.07-2.97 (m, 0.5H), 2.30-2.19 (m, 1H),2.16-2.06 (m, 1H), 1.99-1.87 (m, 1H), 1.68-1.51 (m, 1H).

Example 58:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide[4-[[(2-Fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 2-fluoro-4-methoxybenzoyl chloride(332 mg, 1.76 mmol) gave[4-[[(2-fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (253mg, 0.67 mmol, 42% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 303.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]boronic acid (205mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave, after further purification by flash columnchromatography (DCM/MeOH 100:0 to 90:10), tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(235 mg, 0.33 mmol, 72% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 576.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-4-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(235 mg, 0.41 mmol) gave, after further purification by flash columnchromatography (DCM/7N NH₃ in MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide(176 mg, 0.33 mmol, 82% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.12 min, m/z 476.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide(176 mg, 0.37 mmol) gave, purification by flash column chromatography(DCM/MeOH 100:0 to 90:10),N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide(40 mg, 0.07 mmol, 18% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 530.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.73-8.66(m, 1H, NH), 8.26 (s, 1H, ArH), 7.70 (d, J 8.7 Hz, 1H, ArH), 7.67-7.61(m, 2H, ArH), 7.53-7.46 (m, 2H, ArH), 6.93 (dd, J 13.0, 2.4 Hz, 1H,ArH), 6.87 (dd, J 8.7, 2.4 Hz, 1H, ArH), 6.90-6.66 (m, 1H), 6.17-6.02(m, 1H), 5.74-5.54 (m, 1H), 4.77-4.63 (m, 1H), 4.57 (d, J 5.9 Hz, 2H),4.59-4.49 (m, 0.5H), 4.25-4.15 (m, 1H), 4.11-4.02 (m, 0.5H), 3.82 (s,3H), 3.75-3.65 (m, 0.5H), 3.27-3.13 (m, 1H), 3.06-2.94 (m, 0.5H),2.32-2.19 (m, 1H), 2.17-2.06 (m, 1H), 1.97-1.87 (m, 1H), 1.67-1.49 (m,1H).

Example 59:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzamide[4-[[(2-Methylbenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, o-toluoylchloride (247 mg, 1.60 mmol) and[4-(aminomethyl)phenyl]boronic acid hydrochloride (300 mg, 1.60 mmol)afforded the title compound (290 mg, 1.08 mmol, 67% yield).

UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 269.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-methylbenzoyl)amino]methyl]phenyl]boronic acid (290 mg, 1.08mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded the title compound (160 mg, 0.30 mmol, 66%yield) as an orange-red solid.

UPLC-MS (ES⁺, Short acidic): 1.66 min, m/z 542.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(160 mg, 0.30 mmol) afforded the title compound (118 mg, 0.27 mmol, 58%yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 442.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzamide(118 mg, 0.27 mmol) afforded the title compound (13 mg, 0.03 mmol, 9%yield) as a colourless solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 496.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.04 min, m/z 496.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.86 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.69-7.62 (m, 2H, ArH), 7.54-7.49(m, 2H, ArH), 7.43-7.38 (m, 1H, ArH), 7.37-7.31 (m, 1H, ArH), 7.28-7.22(m, 2H, ArH), 6.92-6.66 (m, 1H), 6.18-6.01 (m, 1H), 5.75-5.55 (m, 1H),4.79-4.64 (m, 1H), 4.60-4.49 (m, 0.5H), 4.53 (d, J 6.0 Hz, 2H),4.27-4.14 (m, 1H), 4.12-4.03 (m, 0.5H), 3.76-3.65 (m, 0.5H), 3.26-3.14(m, 1H), 3.06-2.95 (m, 0.5H), 2.36 (s, 3H), 2.30-2.19 (m, 1H), 2.18-2.06(m, 1H), 2.00-1.87 (m, 1H), 1.68-1.49 (m, 1H).

Example 60:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide[3-[[(2-Methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [3-(aminomethyl)phenyl]boronic acidhydrochloride (248 mg, 1.32 mmol) and 2-methoxy-5-methylbenzoic acid(200 mg, 1.20 mmol) gave[3-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid (284mg, 0.95 mmol, 79% yield) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 299.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (230 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260 mg, 0.45 mmol, quantitative) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.80 min, m/z 572.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(2-methoxy-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260 mg, 0.46 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(202 mg, 0.43 mmol, 94% yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.22 min, m/z 472.4 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(202 mg, 0.43 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide(52 mg, 0.10 mmol, 23% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 526.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.35 min, m/z 526.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.76 (t, J6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.70-7.42 (m, 5H, ArH), 7.29-7.23(m, 1H, ArH), 7.03 (d, J 8.4 Hz, 1H, ArH), 6.91-6.66 (m, 1H), 6.17-6.01(m, 1H), 5.74-5.54 (m, 1H), 4.78-4.63 (m, 1H), 4.57 (d, J 6.0 Hz, 2H),4.58-4.49 (m, 0.5H), 4.31-4.15 (m, 1H), 4.14-4.03 (m, 0.5H), 3.84 (s,3H), 3.73-3.62 (m, 0.5H), 3.25-3.10 (m, 1H), 3.01-2.90 (m, 0.5H),2.30-2.19 (m, 1H), 2.25 (s, 3H), 2.17-2.07 (m, 1H), 1.96-1.87 (m, 1H),1.67-1.50 (m, 1H).

Example 61:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide[4-[[[4-Ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid

Following general procedure B, 4-aminomethylphenylboronic acidhydrochloride (186 mg, 1.00 mmol) and4-ethoxy-3-(trifluoromethyl)benzoyl chloride (253 mg, 1.00 mmol) gave[4-[[[4-ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (340 mg, 0.93 mmol, 93% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.57 min, m/z 367.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[4-ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (248 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[[4-ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(174 mg, 0.27 mmol, 60% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.86 min, m/z 640.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[4-ethoxy-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(174 mg, 0.27 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide(118 mg, 0.22 mmol, 80% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 540.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzenesulfonamide(126 mg, 0.26 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide(7 mg, 0.01 mmol, 5% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.61 min, m/z 594.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.67 min, m/z 594.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.21 (t, J5.9 Hz, 1H, NH), 8.26 (s, 1H, ArH), 8.22-8.17 (m, 2H, ArH), 7.67-7.60(m, 2H, ArH), 7.52-7.47 (m, 2H, ArH), 7.39-7.34 (m, 1H, ArH), 6.88-6.63(m, 1H), 6.17-6.00 (m, 1H), 5.75-5.53 (m, 1H), 4.77-4.63 (m, 1H), 4.57(d, J 5.9 Hz, 2H), 4.55-4.48 (m, 0.5H), 4.29-4.14 (m, 1H), 4.25 (q, J7.0 Hz, 2H), 4.12-4.02 (m, 0.5H), 3.76-3.63 (m, 0.5H), 3.26-3.14 (m,1H), 3.07-2.94 (m, 0.5H), 2.30-2.18 (m, 1H), 2.17-2.05 (m, 1H),1.99-1.88 (m, 1H), 1.67-1.47 (m, 1H), 1.36 (t, J 7.1 Hz, 3H).

Example 62:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide[4-[[(2,6-Difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid

Following general procedure B, 2,6-difluorobenzoyl chloride (0.18 mL,1.41 mmol) and [4-(aminomethyl)-3-fluoro-phenyl]boronic acid (250 mg,1.48 mmol) afforded[4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid(351 mg, 1.14 mmol, 77% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 310.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure C,[4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid(312 mg, 1.01 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(166 mg, 0.29 mmol, 63% yield) as a dark yellow film.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 582.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2,6-difluorobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(166 mg, 0.29 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide(130 mg, 0.27 mmol, 95% yield) as a pale brown foam.

UPLC-MS (ES⁺, Short acidic): 0.98 min, m/z 482.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide(130 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide(22 mg, 0.04 mmol, 15% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 536.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 536.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.34 (t, J5.9 Hz, 1H, NH), 8.29 (s, 1H, ArH), 7.59-7.49 (m, 3H, ArH), 7.49-7.42(m, 1H, ArH), 7.24-7.16 (m, 1H, ArH), 6.92-6.63 (m, 1H), 6.18-6.00 (m,1H), 5.75-5.53 (m, 1H), 4.81-4.65 (m, 1H), 4.58 (d, J 5.9 Hz, 2H),4.57-4.47 (m, 1H), 4.23-4.11 (m, 1H), 4.11-3.99 (m, 0.5H), 3.78-3.68 (m,0.5H), 3.36-3.16 (m, 1H), 3.12-3.00 (m, 0.5H), 2.29-2.18 (m, 1H),2.17-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.68-1.50 (m, 1H).

Example 63:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide[3-Fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid

Following general procedure A, [4-(aminomethyl)-3-fluoro-phenyl]boronicacid (250 mg, 1.48 mmol) and 4-fluoro-2-methoxybenzoic acid (239 mg,1.41 mmol) afforded[3-fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (318 mg, 0.99 mmol, 67% yield) as a dark yellow film.

UPLC-MS (ES⁺, Short acidic): 1.69 min, m/z 322.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure C,[3-fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]boronicacid (324 mg, 1.01 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(260 mg, 0.44 mmol, 97% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.34 min, m/z 594.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(4-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(261 mg, 0.44 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide(217 mg, 0.44 mmol, 100% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 494.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide(217 mg, 0.44 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide(63 mg, 0.12 mmol, 26% yield) as a white crystalline powder.

UPLC-MS (ES⁺, Short acidic): 1.49 min, m/z 548.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.37 min, m/z 548.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.71 (t, J5.9 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.84 (dd, J 8.7, 7.2 Hz, 1H),7.56-7.40 (m, 3H, ArH), 7.09 (dd, J 11.4, 2.4 Hz, 1H), 6.92-6.64 (m,2H), 6.18-6.00 (m, 1H), 5.75-5.52 (m, 1H), 4.81-4.64 (m, 1H), 4.61 (d, J5.9 Hz, 2H), 4.56-4.58 (m, 1H), 4.23-4.11 (m, 1H), 4.10-4.00 (m, 0.5H),3.94 (s, 3H), 3.77-3.66 (m, 0.5H), 3.30-3.15 (m, 1H), 3.12-2.98 (m,0.5H), 2.34-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.98-1.85 (m, 1H),1.68-1.49 (m, 1H).

Example 64:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide[4-[[(3-Cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid

Following general procedure A, 3-cyanobenzoic acid (207 mg, 1.41 mmol)and [4-(aminomethyl)-3-fluoro-phenyl]boronic acid (250 mg, 1.48 mmol)afforded [4-[[(3-cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid(307 mg, 1.03 mmol, 70% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 340.0 [M+MeCN+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure C,[4-[[(3-cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]boronic acid (301 mg,1.01 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(171 mg, 0.30 mmol, 67% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.15 min, m/z 571.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-cyanobenzoyl)amino]methyl]-3-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(171 mg, 0.30 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide(141 mg, 0.30 mmol, 100% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1.04 min, m/z 471.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide(141 mg, 0.30 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide(23 mg, 0.04 mmol, 15% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.39 min, m/z 525.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.10 min, m/z 525.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.30 (t, J5.9 Hz, 1H, NH), 8.36-8.33 (m, 1H), 8.26 (s, 1H, ArH), 8.24-8.19 (m, 1H,ArH), 8.06-8.01 (m, 1H, ArH), 7.75-7.70 (m, 1H, ArH), 7.60-7.54 (m, 1H,ArH), 7.51-7.40 (m, 2H, ArH), 6.93-6.62 (m, 1H), 6.19-5.99 (m, 1H),5.75-5.52 (m, 1H), 4.81-4.65 (m, 1H), 4.61 (d, J 5.9 Hz, 2H), 4.56-4.47(m, 1H), 4.22-4.10 (m, 1H), 4.10-4.00 (m, 0.5H), 3.77-3.65 (m, 0.5H),3.33-3.14 (m, 1H), 3.11-3.01 (m, 0.5H), 2.30-2.18 (m, 1H), 2.17-2.07 (m,1H), 1.98-1.87 (m, 1H), 1.66-1.49 (m, 1H).

Example 65:N-[[4-[4-amino-1-(1-prop-2-enoyl-3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(1E)-4-Bromo-2-fluoro-benzaldehyde oxime

Following general procedure G, 4-bromo-2-fluoro-benzaldehyde oxime (1.00g, 4.93 mmol) afforded (1E)-4-bromo-2-fluoro-benzaldehyde oxime (1.02 g,4.69 mmol, 95% yield) as a white crystalline powder.

UPLC-MS (ES⁺, Short acidic): 1.59 min, m/z 219.8 [M+H]⁺

[3-Fluoro-4-[(E)-hydroxyiminomethyl]phenyl]boronic acid

Following general procedure I, (1E)-4-bromo-2-fluoro-benzaldehyde oxime(4.00 g, 18.4 mmol) afforded[3-fluoro-4-[(E)-hydroxyiminomethyl]phenyl]boronic acid (3.04 g, 16.6mmol, 91% yield) as a white solid.

UPLC-MS (ES⁻, Short acidic): 0.87 min, m/z 182.0 [M−H]⁻

[4-(Aminomethyl)-3-fluoro-phenyl]boronic acid

Following general procedure J,[3-fluoro-4-[(E)-hydroxyiminomethyl]phenyl]boronic acid (4.90 g, 26.8mmol) afforded [4-(aminomethyl)-3-fluoro-phenyl]boronic acid (0.93 g,5.52 mmol, 21% yield) as an off-white solid.

¹H NMR (400 MHz, MeOD-d₄) 7.71-7.34 (m, 3H, ArH), 4.20 (s, 2H)

[3-Fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)-3-fluoro-phenyl]boronicacid (250 mg, 1.48 mmol) and 2-methoxybenzoic acid (214 mg, 1.41 mmol)afforded [3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronicacid (306 mg, 1.01 mmol, 68.3% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 1.56 min, m/z 304.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure C,[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (306mg, 1.01 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(210 mg, 0.37 mmol, 81% yield) as a brown film.

UPLC-MS (ES⁺, Short acidic): 2.26 min, m/z 576.3 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-fluoro-4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(210 mg, 0.36 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(159 mg, 0.33 mmol, 92% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.14 min, m/z 476.2 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-(3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(159 mg, 0.33 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(24 mg, 0.05 mmol, 14% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.28 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.76 (t, J6.0 Hz, 1H, NH), 8.28 (s, 1H, ArH), 7.77 (dd, J 7.6, 1.7 Hz, 1H),7.58-7.40 (m, 4H, ArH), 7.20-7.15 (m, 1H, ArH), 7.08-7.02 (m, 1H, ArH),6.92-6.62 (m, 1H), 6.18-6.00 (m, 1H), 5.76-5.53 (m, 1H), 4.84-4.64 (m,1H), 4.61 (d, J 6.0 Hz, 2H), 4.57-4.45 (m, 1H), 4.24-4.12 (m, 1H),4.10-4.00 (m, 0.5H), 3.91 (s, 3H), 3.77-3.66 (m, 0.5H), 3.34-3.14 (m,1H), 3.11-2.99 (m, 0.5H), 2.31-2.19 (m, 1H), 2.17-2.06 (m, 1H),1.99-1.87 (m, 1H), 1.68-1.49 (m, 1H).

Example 66:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-N-methyl-benzamide[4-[[(2-Fluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (403 mg, 2.15 mmol) and 2-fluorobenzoic acid (274 mg, 1.96mmol) gave [4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid (430mg, 1.2 mmol, 60% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 274.1 [M+H]⁺

4-[[(2-Fluorobenzoyl)-methyl-amino]methyl]phenyl]boronic acid

To a solution of [4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid(430 mg, 1.57 mmol) in DMF (11 mL) was added sodium hydride (195 mg,4.88 mmol). The solution was stirred at room temperature for 1 h under anitrogen atmosphere. After this time, iodomethane (0.3 mL, 4.88 mmol)was added, and the mixture was stirred overnight at room temperature.The reaction was diluted with saturated ammonium chloride (100 mL)before being extracted using ethyl acetate (2×100 mL). The combinedorganic layers were then washed with 0.1M NaOH (100 mL), water (100 mL)and brine (2×100 mL). The yellow/brown solution was then dried overNa₂SO₄ and concentrated under reduced pressure to afford[4-[[(2-fluorobenzoyl)-methyl-amino]methyl]phenyl]boronic acid (390 mg,0.95 mmol, 60% yield) as a yellow oil that solidified upon standing.

UPLC-MS: (ES⁺, Short acidic): 1.44 min, 288.1 m/z [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)-N-methylformamino]methyl]phenyl]-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluorobenzoyl)amino]methyl]phenyl]boronic acid (337 mg, 0.86mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(240 mg, 0.54 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)-N-methylformamino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylate(299 mg, 0.51 mmol, 94% yield) as a dark brown foam.

UPLC-MS (ES⁺, Short acidic): 2.16 min, m/z 560.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-N-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluorobenzoyl)-methyl-amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(299 mg, 0.53 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl]methyl]-2-fluoro-N-methyl-benzamide(215 mg, 0.44 mmol, 83% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 460.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl]-methyl]-2-fluoro-N-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]-pyrimidin-3-yl]phenyl]methyl]-2-fluoro-N-methyl-benzamide(215 mg, 0.47 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-N-methyl-benzamide(42 mg, 0.08 mmol, 17% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 514.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.17 min, m/z 514.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.30-8.24(m, 1H, ArH), 7.73-7.67 (m, 1H, ArH), 7.66-7.61 (m, 1H, ArH), 7.57-7.46(m, 3H, ArH), 7.38-7.26 (m, 3H, ArH), 6.93-6.63 (m, 1H), 6.19-6.00 (m,1H), 5.76-5.52 (m, 1H), 4.81 (s, 1.2H), 4.78-4.64 (m, 1H), 4.60-4.51 (m,1H), 4.49 (s, 0.8H), 4.26-4.15 (m, 1H), 4.13-4.03 (m, 0.5H), 3.76-3.65(m, 0.5H), 3.28-3.14 (m, 1H), 3.06-3.00 (m, 0.5H), 2.99 (s, 1.2H), 2.83(s, 1.8H), 2.31-2.20 (m, 1H), 2.18-2.08 (m, 1H), 1.98-1.89 (m, 1H),1.68-1.51 (m, 1H).

Example 67:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide[4-[[(3-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 3-methoxybenzoyl chloride (0.25mL, 1.76 mmol) gave [4-[[(3-methoxybenzoyl)amino]methyl]phenyl]boronicacid (435 mg, 1.07 mmol, 68% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.27 min, m/z 285.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(3-methoxybenzoyl)amino]methyl]phenyl]boronic acid (144 mg, 0.51mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150 mg, 0.36 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(3-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(149 mg, 0.28 mmol, 79% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 558.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(149 mg, 0.27 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide(69 mg, 0.16 mmol, 56% yield) as a yellow oil.

UPLC-MS (ES⁺, Short acidic): 1.10 min, m/z 458.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide(69 mg, 0.15 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide(10 mg, 0.02 mmol, 13% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 512.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.05 min, m/z 512.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.10 (t, J6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.53-7.45(m, 4H, ArH), 7.40 (dd, J 8.0, 7.8 Hz, 1H7.11 (ddd, J 8.0, 2.7, 1.0 Hz,1H6.93-6.63 (m, 1H), 6.17-6.00 (m, 1H), 5.75-5.54 (m, 1H), 4.79-4.62 (m,1H), 4.56 (d, J 6.0 Hz, 2H), 4.55-4.50 (m, 0.5H), 4.25-4.15 (m, 1H),4.12-4.02 (m, 0.5H), 3.81 (s, 3H), 3.75-3.62 (m, 0.5H), 3.25-3.12 (m,1H), 3.07-2.94 (m, 0.5H), 2.30-2.20 (m, 1H), 2.16-2.06 (m, 1H),1.98-1.86 (m, 1H), 1.67-1.50 (m, 1H).

Example 68:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide[3-[[(2,6-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, 2,6-difluorobenzoyl chloride (0.14 mL,1.13 mmol) and (3-(aminomethyl)phenyl)boronic acid hydrochloride (212mg, 1.13 mmol) afforded[3-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]boronic acid (143 mg, 0.49mmol, 43% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.24 min, m/z 291.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[3-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]boronic acid (147 mg, 0.51mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(150 mg, 0.34 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(170 mg, 0.30 mmol, 89% yield) as an off-white foam.

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 564.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(2,6-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(170 mg, 0.30 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(141 mg, 0.30 mmol, quantitative) as a dark yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.08 min, m/z 464.3 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(141 mg, 0.30 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide(47 mg, 0.09 mmol, 30% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 518.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.98 min, m/z 518.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.32 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.68-7.63 (m, 1H, ArH), 7.59-7.48(m, 3H, ArH), 7.47-7.42 (m, 1H, ArH), 7.21-7.13 (m, 2H, ArH), 6.93-6.66(m, 1H), 6.20-6.01 (m, 1H), 5.76-5.55 (m, 1H), 4.81-4.64 (m, 1H),4.62-4.47 (m, 2.5H), 4.31-4.18 (m, 1H), 4.13-4.05 (m, 0.5H), 3.74-3.65(m, 0.5H), 3.25-3.13 (m, 1H), 3.03-2.88 (m, 0.5H), 2.35-2.20 (m, 1H),2.18-2.06 (m, 1H), 1.98-1.88 (m, 1H), 1.69-1.51 (m, 1H).

Example 69:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzamide[4-[[[2-(Trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.6 mmol) and 2-(trifluoromethyl)benzoyl chloride(0.26 mL, 1.76 mmol) afforded the title compound (348 mg, 1.08 mmol, 67%yield).

UPLC-MS (ES⁺, short acidic): 1.32 min, m/z 324.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronic acid (348mg, 1.08 mmol) afforded the title compound (310 mg, 0.52 mmol, 92%yield) as an orange solid.

UPLC-MS (ES⁺, Short acidic): 2.17 min, m/z 596.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[[2-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(310 mg, 0.52 mmol) afforded the title compound (210 mg, 0.42 mmol, 81%yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.11 min, m/z 496.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzamide(210 mg, 0.42 mmol) afforded the title compound (54 mg, 0.10 mmol, 23%yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 550.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 550.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.11 (t, J5.9 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.83-7.78 (m, 1H, ArH), 7.78-7.72(m, 1H, ArH), 7.70-7.58 (m, 4H, ArH), 7.55-7.48 (m, 2H, ArH), 6.92-6.65(m, 1H), 6.18-6.00 (m, 1H), 5.73-5.53 (m, 1H), 4.79-4.62 (m, 1H),4.61-4.47 (m, 2.5H), 4.28-4.15 (m, 1H), 4.12-4.01 (m, 0.5H), 3.78-3.64(m, 0.5H), 3.28-3.12 (m, 1H), 3.07-2.95 (m, 0.5H), 2.36-2.19 (m, 1H),2.19-2.06 (m, 1H), 1.98-1.86 (m, 1H), 1.67-1.50 (m, 1H).

Example 70:N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-N-methyl-benzamide[4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 2-methoxybenzoic acid (0.25 mL, 1.76mmol) and [4-(aminomethyl)phenyl]boronic acid hydrochloride (300 mg,1.60 mmol) afforded the title compound (370 mg, 1.3 mmol, 81%).

UPLC-MS (ES⁺, short acidic): 1.31 min, m/z 285.9 [M+H]⁺

[4-[[(2-Methoxybenzoyl)-methyl-amino]methyl]phenyl]boronic acid

To a solution of [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(370 mg, 1.3 mmol) in DMF (15 mL) was added sodium hydride (160 mg, 4.00mmol). The solution was stirred at 0° C. for 1 h under nitrogen.Iodomethane (0.3 mL, 4.00 mmol) was then added, and the mixture wasstirred overnight at room temperature. The reaction was diluted withsaturated ammonium chloride (100 mL) before being extracted with EtOAc(2×100 mL). The combined organic layers were then washed with 0.1 M NaOH(100 mL), water (100 mL) and brine (100 mL). The light yellow solutionwas then dried over Na₂SO₄ and concentrated in vacuo to the titlecompound (167 mg, 0.60 mmol, 43% yield) as a light yellow solid.

UPLC-MS (ES⁺, short acidic): 1.45 min, 300.1 m/z [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-methoxybenzoyl)-methyl-amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-methoxybenzoyl)-methyl-amino]methyl]phenyl]boronic acid (167 mg,0.56 mmol) afforded the title compound (79 mg, 0.14 mmol, 31% yield) asan orange solid.

UPLC-MS (ES⁺, Short acidic): 2.14 min, m/z 572.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-N-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-methoxybenzoyl)-methyl-amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(79.0 mg, 0.14 mmol) afforded the title compound (60 mg, 0.13 mmol, 92%yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 472.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-N-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-N-methyl-benzamide(60 mg, 0.13 mmol afforded the title compound (2 mg, 0.01 mmol, 3%yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 526.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.16 min, m/z 526.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, mixture of conformers) 8.30-8.25 (m,1H, ArH), 7.73-7.67 (m, 1H, ArH), 7.66-7.59 (m, 1H, ArH), 7.55-7.49 (m,1H, ArH), 7.46-7.36 (m, 1H, ArH), 7.35-7.30 (m, 1H, ArH), 7.30-7.24 (m,1H, ArH), 7.15-6.96 (m, 2H, ArH), 6.92-6.66 (m, 1H), 6.20-6.00 (m, 1H),5.74-5.54 (m, 1H), 4.99-4.87 (m, 0.5H), 4.79-4.49 (m, 2.5H), 4.57 (d, J5.9 Hz, 2H), 4.39 (s, 0.8H), 4.27-4.13 (m, 1H), 4.13-4.01 (m, 0.5H),3.86 (s, 2H), 3.81 (s, 1H), 3.75-3.66 (m, 0.5H), 3.25-3.14 (m, 1H),3.07-2.96 (m, 0.5H), 2.93 (s, 1.2H), 2.73 (s, 2H), 2.31-2.19 (m, 1H),2.18-2.07 (m, 1H), 1.99-1.88 (m, 1H), 1.67-1.51 (m, 1H).

Example 71:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide[3-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [3-(aminomethyl)phenyl]boronic acidhydrochloride (271 mg, 1.45 mmol) and 2-methoxybenzoic acid (200 mg,1.31 mmol) gave [3-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid(286 mg, 1.00 mmol, 76% yield) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.32 min, m/z 285.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-fluoro-3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]boronicacid (230 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol), gave tert-butyl(3R)-3-[4-amino-3-[3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(236 mg, 0.42 mmol, 94% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.70 min, m/z 558.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(236 mg, 0.42 mmol) gave crudeN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(196 mg, 0.42 mmol, quantitative) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 458.3 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(196 mg, 0.43 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(112 mg, 0.22 mmol, 51% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 512.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.14 min, m/z 512.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.79 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.76 (dd, J 7.7, 1.8 Hz, 1H, ArH),7.67-7.62 (m, 1H, ArH), 7.57-7.43 (m, 4H, ArH), 7.17-7.12 (m, 1H, ArH),7.02 (dt, J 7.5, 1.0 Hz, 1H, ArH), 6.91-6.67 (m, 1H), 6.17-6.01 (m, 1H),5.74-5.55 (m, 1H), 4.78-4.64 (m, 1H), 4.58 (d, J 6.0 Hz, 2H), 4.55-4.51(m, 0.5H), 4.30-4.16 (m, 1H), 4.13-4.03 (m, 0.5H), 3.87 (s, 3H),3.72-3.62 (m, 0.5H), 3.25-3.10 (m, 1H), 3.03-2.91 (m, 0.5H), 2.31-2.19(m, 1H), 2.17-2.07 (m, 1H), 1.98-1.87 (m, 1H), 1.68-1.50 (m, 1H).

Example 72:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide[3-[[(3-Cyanobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, 3-cyanobenzoic acid (200 mg, 1.36 mmol)and [3-(aminomethyl)phenyl]boronic acid hydrochloride (280 mg, 1.50mmol) gave crude [3-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronic acid(461 mg, 1.65 mmol, assumed quantitative) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 280.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[3-[[(3-cyanobenzoyl)amino]methyl]phenyl]boronic acid (236 mg, 0.84mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(250 mg, 0.56 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(255 mg, 0.46 mmol, 82% yield) as a yellow foam

UPLC-MS (ES⁺, Short acidic): 1.64 min, m/z 553.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(3-cyanobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(255 mg, 0.46 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(197 mg, 0.44 mmol, 94% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.07 min, m/z 453.4 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(197 mg, 0.44 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide(51.2 mg, 0.10 mmol, 23% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.36 min, m/z 507.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.00 min, m/z 507.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.33 (t, J5.6 Hz, 1H, NH), 8.34-8.32 (m, 1H), 8.26 (s, 1H, ArH), 8.23-8.19 (m, 1H,ArH), 8.04-8.00 (m, 1H, ArH), 7.74-7.68 (m, 1H, ArH), 7.66-7.61 (m, 1H,ArH), 7.59-7.43 (m, 3H, ArH), 6.91-6.64 (m, 1H), 6.17-5.99 (m, 1H),5.74-5.52 (m, 1H), 4.79-4.62 (m, 1H), 4.61-4.47 (m, 2.5H), 4.27-4.14 (m,1H), 4.12-4.02 (m, 0.5H), 3.73-3.62 (m, 0.5H), 3.25-3.11 (m, 1H),3.05-2.93 (m, 0.5H), 2.30-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.98-1.87 (m,1H), 1.67-1.51 (m, 1H).

Example 73:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide[3-[[(2,5-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, (3-(aminomethyl)phenyl)boronic acidhydrochloride (318 mg, 1.70 mmol) and 2,5-difluorobenzoyl chloride (0.21mL, 1.70 mmol) afforded[3-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (112 mg, 0.39mmol, 23% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.33 min, m/z 291.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(170 mg, 0.38 mmol) and[3-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (167 mg, 0.57mmol) afforded tert-butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(135 mg, 0.24 mmol, 63% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.72 min, m/z 564.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(135 mg, 0.24 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(98 mg, 0.21 mmol, 89% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.14 min, m/z 464.3 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(98 mg, 0.21 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(29 mg, 0.06 mmol, 26% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 518.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.15 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.07-8.99(m, 1H, NH), 8.27 (s, 1H, ArH), 7.67-7.60 (m, 1H, ArH), 7.59-7.31 (m,6H, ArH), 6.92-6.67 (m, 1H), 6.17-6.02 (m, 1H), 5.75-5.55 (m, 1H),4.78-4.64 (m, 1H), 4.59-4.50 (m, 2.5H), 4.30-4.16 (m, 1H), 4.13-4.03 (m,0.5H), 3.75-3.63 (m, 0.5H), 3.25-3.10 (m, 1H), 3.03-2.91 (m, 0.5H),2.31-2.19 (m, 1H), 2.17-2.07 (m, 1H), 1.98-1.87 (m, 1H), 1.67-1.49 (m,1H).

Example 74:N-[[4-[4-amino-1-[(3R)-1-[[(2R)-oxiran-2-yl]methyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(110 mg, 0.24 mmol) in DMF (1 mL) were added successivelyN,N-diisopropylethylamine (0.05 mL, 0.26 mmol) and (S)-glycidyl nosylate(69 mg, 0.26 mmol). The mixture was stirred at room temperature for 2days, quenched with an aqueous sodium bicarbonate solution (20 mL) andthen extracted (×3) with EtOAc. The combined organics were dried overNa₂SO₄, filtered and concentrated. Further purification by flash columnchromatography (1-10% 1N NH₃ in MeOH/EtOAc) gaveN-[[4-[4-amino-1-[(3R)-1-[[(2R)-oxiran-2-yl]methyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(15 mg, 0.03 mmol, 12% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 514.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.55 min, m/z 514.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.25 (s, 1H, ArH), 7.77 (dd, J 7.6, 1.7 Hz, 1H, ArH),7.66-7.60 (m, 2H, ArH), 7.54-7.45 (m, 3H, ArH), 7.18-7.13 (m, 1H, ArH),7.04 (dt, J 7.6, 1.0 Hz, 1H, ArH), 4.93-4.72 (m, 1H), 4.58 (d, J 6.1 Hz,2H), 3.90 (s, 3H), 3.21-2.68 (m, 5H), 2.46-1.91 (m, 6H), 1.89-1.77 (m,1H), 1.76-1.59 (m, 1H).

Example 75:N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamideN-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide

Under N₂, a stirred solution of sodium hydride (60% dispersed in mineraloil) (54 mg, 1.35 mmol) in THF (6 mL) was cooled to 0° C. using an icebath before 3-(trifluoromethyl)benzamide (153 mg, 0.81 mmol) was added.The resulting solution was stirred at this temperature for 1 h30 before2-[3-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200mg, 0.67 mmol) was added and the solution allowed to warm to roomtemperature and was stirred overnight. The solution was diluted withEtOAc (20 mL) and quenched with a saturated ammonium chloride solution(20 mL) before being partitioned. The aqueous layer was washed withEtOAc (3×10 mL) before the combined organics were washed with water (30mL) and brine (30 mL). The combined organics were dried (Na₂SO₄),filtered and concentrated to dryness in vacuo to afford crudeN-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide(400 mg, 0.56 mmol, 84% yield) as a clear oil that crystallised uponstanding.

UPLC-MS (ES⁺, Short acidic): 1.99 min, m/z 406 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[[3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide(274 mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[3-[[[3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(129 mg, 0.22 mmol, 48% yield) as a dark yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.84 min, m/z 596.5 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[[3-(trifluoromethyl)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(129 mg, 0.22 mmol) gaveN-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(99 mg, 0.20 mmol, 92% yield) as a yellow film.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 496.4 [M+H]⁺

N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide

Following general procedure F,N-[[3-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(99 mg, 0.20 mmol) affordedN-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide(39 mg, 0.07 mmol, 36% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.54 min, m/z 550.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.47 min, m/z 550.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.37 (t, J5.4 Hz, 1H, NH), 8.31-8.17 (m, 3H, ArH), 7.95-7.90 (m, 1H, ArH),7.78-7.68 (m, 1H, ArH), 7.67-7.62 (m, 1H, ArH), 7.59-7.43 (m, 3H, ArH),6.92-6.64 (m, 1H), 6.17-6.01 (m, 1H), 5.74-5.54 (m, 1H), 4.80-4.63 (m,1H), 4.61-4.49 (m, 2.5H), 4.29-4.15 (m, 1H), 4.12-4.01 (m, 0.5H),3.72-3.61 (m, 0.5H), 3.25-3.11 (m, 1H), 3.05-2.91 (m, 0.5H), 2.32-2.19(m, 1H), 2.17-2.06 (m, 1H), 1.97-1.87 (m, 1H), 1.67-1.49 (m, 1H).

Example 76:N-[[5-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide[3-[[(2,5-Difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]boronic acid

Following general procedure A, [3-(aminomethyl)-4-fluoro-phenyl]boronicacid (200 mg, 1.18 mmol) and 2,5-difluorobenzoyl chloride (0.14 mL, 1.12mmol) afforded[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]boronic acid(341 mg, 1.10 mmol, 93% yield) as a pale yellow film.

UPLC-MS (ES⁺, Short acidic): 1.63 min, m/z 310.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) and[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]boronic acid(209 mg, 0.68 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(252 mg, 0.43 mmol, 96% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.25 min, m/z 582.3 [M+H]⁺

N-[[5-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(255 mg, 0.44 mmol) gaveN-[[5-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide(48 mg, 0.10 mmol, 23% yield) as a pale brown foam.

UPLC-MS (ES⁺, Short acidic): 1.27 min, m/z 482.2 [M+H]⁺

N-[[5-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure F,N-[[5-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide(155 mg, 0.32 mmol) affordedN-[[5-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide(59 mg, 0.11 mmol, 34% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.46 min, m/z 536.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.27 min, m/z 536.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.05-8.99(m, 1H, NH), 8.25 (s, 1H, ArH), 7.74-7.67 (m, 1H, ArH), 7.64-7.55 (m,1H, ArH), 7.49-7.42 (m, 1H, ArH), 7.42-7.32 (m, 3H, ArH), 6.91-6.63 (m,1H), 6.17-6.01 (m, 1H), 5.74-5.54 (m, 1H), 4.77-4.63 (m, 1H), 4.61-4.49(m, 2.5H), 4.30-4.14 (m, 1H), 4.12-4.04 (m, 0.5H), 3.72-3.61 (m, 0.5H),3.25-3.10 (m, 1H), 3.04-2.90 (m, 0.5H), 2.30-2.18 (m, 1H), 2.16-2.06 (m,1H), 1.97-1.85 (m, 1H), 1.68-1.50 (m, 1H).

Example 77:N-[[5-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide[4-Fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [3-(aminomethyl)-4-fluoro-phenyl]boronicacid (200 mg, 1.18 mmol) and 2-methoxybenzoic acid (0.12 mL, 1.12 mmol)afforded [4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronicacid (269 mg, 0.18 mmol, 15% yield) as a colourless film.

UPLC-MS (ES⁺, Short acidic): 1.60 min, m/z 304.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) and[3-[[(2,5-difluorobenzoyl)amino]methyl]-4-fluoro-phenyl]boronic acid(209 mg, 0.68 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(69 mg, 0.12 mmol, 27% yield) as a light brown film.

UPLC-MS (ES⁺, Short acidic): 2.24 min, m/z 576.3 [M+H]⁺

N-[[5-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-fluoro-3-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(69 mg, 0.12 mmol) affordedN-[[5-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(48 mg, 0.10 mmol, 84% yield) as a pale brown foam.

UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 476.2 [M+H]⁺

N-[[5-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[5-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-methoxy-benzamide(48 mg, 0.10 mmol) affordedN-[[5-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide(20 mg, 0.04 mmol, 36% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 530.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.27 min, m/z 530.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J5.9 Hz, 1H, NH), 8.24 (s, 1H, ArH), 7.74 (dd, J 7.7, 1.8 Hz, 1H, ArH),7.71-7.65 (m, 1H, ArH), 7.60-7.54 (m, 1H, ArH), 7.50-7.43 (m, 1H, ArH),7.40-7.33 (m, 1H, ArH), 7.16-7.11 (m, 1H, ArH), 7.05-6.99 (m, 1H, ArH),6.90-6.65 (m, 1H), 6.16-6.00 (m, 1H), 5.74-5.53 (m, 1H), 4.75-4.46 (m,4H), 4.30-4.14 (m, 1H), 4.12-4.01 (m, 0.5H), 3.84 (s, 3H), 3.70-3.59 (m,0.5H), 3.23-3.09 (m, 1H), 2.99-2.86 (m, 0.5H), 2.30-2.17 (m, 1H),2.15-2.05 (m, 1H), 1.96-1.84 (m, 1H), 1.68-1.48 (m, 1H).

Example 78:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methyl-benzamide[4-[[(2-Fluoro-3-methyl-benzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (107 mg, 0.57 mmol) and 2-fluoro-3-methylbenzoic acid(0.08 mL, 0.52 mmol) gave the title compound (67 mg, 0.23 mmol, 45%yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 287.8 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-3-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) and2-fluoro-3-methyl-N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide(249 mg, 0.68 mmol) gave the title compound (243 mg, 0.43 mmol, 96%yield) as a pale yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.73 min, m/z 560.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-3-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(243 mg, 0.43 mmol) gave the title compound (177 mg, 0.39 mmol, 89%yield) as a yellow foam.

UPLC-MS (ES⁺, Short acidic): 1.17 min, m/z 460.3 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methyl-benzamide(177 mg, 0.39 mmol) and acrylic acid (26 μL, 0.39 mmol) gave the titlecompound (5 mg, 0.09 mmol, 2% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 514.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 514.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.96-8.88(m, 1H, NH), 8.27 (s, 1H, ArH), 7.69-7.58 (m, 2H, ArH), 7.54-7.38 (m,4H, ArH), 7.23-7.13 (m, 1H, ArH), 6.90-6.63 (m, 1H), 6.16-6.01 (m, 1H),5.75-5.54 (m, 1H), 4.78-4.63 (m, 1H), 4.60-4.48 (m, 2.5H), 4.26-4.13 (m,1H), 4.12-4.01 (m, 0.5H), 3.76-3.63 (m, 0.5H), 3.28-3.14 (m, 1H),3.07-2.96 (m, 0.5H), 2.31-2.20 (m, 1H), 2.16-2.07 (m, 1H), 2.00-1.86 (m,1H), 1.67-1.45 (m, 1H).

Example 79:N-[[4-[4-amino-1-[(3R)-1-propanoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideN-[[4-[4-Amino-1-[(3R)-1-propanoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.33 mmol) and propionic acid (0.02 mL, 0.33 mmol) gave, afterfurther purification by flash column chromatography (DCM/MeOH 100:0 to90:10),N-[[4-[4-amino-1-[(3R)-1-propanoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(80 mg, 0.14 mmol, 43% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.42 min, m/z 514.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.18 min, m/z 514.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.26 (d, J 9.9 Hz, 1H, ArH), 7.77 (dd, J 7.6, 1.8 Hz,1H, ArH), 7.67-7.60 (m, 2H, ArH), 7.54-7.45 (m, 3H, ArH), 7.18-7.14 (m,1H, ArH), 7.05 (td, J 7.6, 1.0 Hz, 1H, ArH), 4.79-4.68 (m, 0.5H),4.67-4.46 (m, 4H), 4.27-4.18 (m, 0.5H), 4.05-3.98 (m, 0.5H), 3.94-3.81(m, 4.5H), 3.61-3.51 (m, 0.5H), 3.14-3.05 (m, 1H), 2.88-2.79 (m, 0.5H),2.43-2.17 (m, 4H), 2.16-2.05 (m, 1H), 1.94-1.82 (m, 1H), 1.69-1.43 (m,1H), 1.06-0.90 (m, 3H).

Example 80:N-[[4-[4-amino-1-[(3R)-1-(2-cyanoacetyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.33 mmol) and cyanoacetic acid (28 mg, 0.33 mmol gaveN-[[4-[4-amino-1-[(3R)-1-(2-cyanoacetyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(49 mg, 0.08 mmol, 25% yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.37 min, m/z 525.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.03 min, m/z 525.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.78 (t, J6.1 Hz, 1H, NH), 8.26 (t, J 7.2 Hz, 1H, ArH), 7.77 (dd, J 7.7, 1.8 Hz,1H, ArH), 7.67-7.61 (m, 2H, ArH), 7.54-7.45 (m, 3H, ArH), 7.19-7.14 (m,1H, ArH), 7.05 (td, J 7.6, 1.0 Hz, 1H, ArH), 4.91-4.54 (m, 1H), 4.59 (d,J 6.1 Hz, 2H), 4.46-4.38 (m, 0.5H), 4.18-3.85 (m, 6H), 3.78-3.63 (m,1H), 3.25-3.11 (m, 1H), 3.03-2.92 (m, 1H), 2.28-2.04 (m, 2H), 1.94-1.46(m, 2H).

Example 81:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide[4-[[(2,5-Difluorobenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure B, [4-(aminomethyl)phenyl]boronic acidhydrochloride (300 mg, 1.60 mmol) and 2,5-difluorobenzoyl chloride (0.22mL, 1.76 mmol) afforded the title compound (390 mg, 1.07 mmol, 67%yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.31 min, m/z 291.8 [M+H]⁺

[4-[[(2,5-Difluorobenzoyl)-methyl-amino]methyl]phenyl]boronic acid

To a solution of sodium hydride (188 mg, 4.69 mmol) in DMF (13 mL) wasadded [4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (390mg, 1.34 mmol) and was stirred at room temperature for 1 h undernitrogen. Iodomethane (0.25 mL, 4.02 mmol) was added, and the mixturewas stirred for 3 h at room temperature then diluted with saturatedammonium chloride (100 mL) and extracted with ethyl acetate (2×100 mL).The combined organics were then washed with 0.1 M NaOH (100 mL), water(100 mL) and brine (2×100 mL), dried over Na₂SO₄, filtered, andconcentrated to yield the title compound (201 mg, 0.66 mmol, 49% yield)as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.35 min, m/z 305.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)-methyl-amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2,5-difluorobenzoyl)-methyl-amino]methyl]phenyl]boronic acid (0.17mL, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave the title compound (248 mg, 0.43 mmol, 95%yield) as an orange foam.

UPLC-MS (ES⁺, Short acidic): 1.74 min, m/z 578.5 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(229 mg, 0.41 mmol) gave the title compound (138 mg, 0.29 mmol, 65%yield) as a white foam.

UPLC-MS (ES⁺, Short acidic): 1.20 min, m/z 478.2 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide(138 mg, 0.29 mmol) and acrylic acid (0.02 mL, 0.29 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide(88 mg, 0.15 mmol, 52% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 532.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.25 min, m/z 532.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, mixture of conformers) 8.27 (s, 1H,ArH), 7.72-7.59 (m, 2H, ArH), 7.53-7.47 (m, 1H, ArH), 7.47-7.29 (m, 4H,ArH), 6.92-6.62 (m, 1H), 6.18-6.00 (m, 1H), 5.73-5.53 (m, 1H), 4.79 (s,1.2H), 4.77-4.62 (m, 1H), 4.60-4.50 (m, 0.5H), 4.49 (s, 0.8H), 4.26-4.15(m, 1H), 4.12-4.02 (m, 0.5H), 3.77-3.64 (m, 0.5H), 3.27-3.12 (m, 1H),3.07-2.93 (m, 1.7H), 2.85-2.78 (m, 2H), 2.31-2.20 (m, 1H), 2.17-2.07 (m,1H), 1.98-1.87 (m, 1H), 1.67-1.48 (m, 1H).

Example 82:N-[[4-[4-amino-1-[(3R)-1-(cyanomethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideN-[[4-[4-Amino-1-[(3R)-1-(cyanomethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-methyl]-2-methoxy-benzamide

To a stirred solution ofN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol)in MeCN (5 mL) at 0° C. was added bromoacetonitrile (0.02 mL, 0.33mmol). The reaction mixture was then stirred at 0-10° C. for 1.5 h undera nitrogen atmosphere. The reaction mixture was then diluted with DCM,washed with H₂O (2×10 mL), dried through a phase separator cartridge andconcentrated under reduced pressure. Further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 90:10) gaveN-[[4-[4-amino-1-[(3R)-1-(cyanomethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(66 mg, 0.12 mmol, 37% yield) as a pale brown solid.

UPLC-MS (ES⁺, Short acidic): 1.44 min, m/z 497.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.19 min, m/z 497.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.25 (s, 1H, ArH), 7.77 (dd, J 7.7, 1.8 Hz, 1H, ArH),7.68-7.62 (m, 2H, ArH), 7.53-7.48 (m, 3H, ArH), 7.18-7.14 (m, 1H, ArH),7.04 (td, J 7.7, 1.0 Hz, 1H, ArH), 4.87-4.76 (m, 1H), 4.59 (d, J 6.1 Hz,2H), 3.91 (s, 3H), 3.84 (d, J 17.1 Hz, 1H), 3.78 (d, J 17.1 Hz, 1H),3.07-2.97 (m, 1H), 2.89-2.79 (m, 1H), 2.70-2.59 (m, 1H), 2.28-2.16 (m,1H), 2.04-1.94 (m, 2H), 1.91-1.82 (m, 1H), 1.77-1.61 (m, 1H).

Example 83:N-[[4-[4-amino-1-[(3R)-1-(2-cyanoethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideN-[[4-[4-Amino-1-[(3R)-1-(2-cyanoethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a stirred solution ofN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(150 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol)in DCM (5 mL) was added 3-bromopropionitrile (0.03 mL, 0.33 mmol). Thereaction was then stirred at room temperature for 48 h under a nitrogenatmosphere. The reaction mixture was then diluted with DCM, washed withH₂O (2×10 mL), dried through a phase separator cartridge andconcentrated under reduced pressure. Further purification by flashcolumn chromatography (DCM/MeOH 100:0 to 90:10) gaveN-[[4-[4-amino-1-[(3R)-1-(2-cyanoethyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(37 mg, 0.06 mmol, 20% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.23 min, m/z 511.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.60 min, m/z 511.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.25 (s, 1H, ArH), 7.77 (dd, J 7.6, 1.8 Hz, 1H, ArH),7.65-7.61 (m, 2H, ArH), 7.53-7.45 (m, 3H, ArH), 7.18-7.14 (m, 1H, ArH),7.04 (td, J 7.6, 0.9 Hz, 1H, ArH), 4.84-4.73 (m, 1H), 4.59 (d, J 6.1 Hz,2H), 3.91 (s, 3H), 3.10-3.01 (m, 1H), 2.97-2.88 (m, 1H), 2.72-2.43 (m,5H), 2.12-1.94 (m, 3H), 1.87-1.77 (m, 1H), 1.72-1.58 (m, 1H).

Example 84:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzamidetert-Butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(2-fluoro-5-methyl-benzoyl)amino]methyl]phenyl]boronic acid (194mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave the title compound (108 mg, 0.19 mmol, 43%yield) as an orange foam.

UPLC-MS (ES⁺, Short acidic): 2.00 min, m/z 560.5 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(229 mg, 0.41 mmol) gave the title compound (88 mg, 0.19 mmol, 99%yield) as a white foam.

UPLC-MS (ES⁺, Short acidic): 1.18 min, m/z 460.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzamide(88 mg, 0.19 mmol) and acrylic acid (13 μL, 0.19 mmol) gave the titlecompound (55 mg, 0.10 mmol, 53% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 3.24 min, m/z 514.5 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 1.46 min, m/z 514.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.95-8.85(m, 1H, NH), 8.26 (s, 1H, ArH), 7.69-7.61 (m, 2H, ArH), 7.53-7.45 (m,3H, ArH), 7.36-7.30 (m, 1H, ArH), 7.19 (dd, J 10.5, 8.4 Hz, 1H, ArH),6.92-6.63 (m, 1H), 6.18-5.99 (m, 1H), 5.75-5.51 (m, 1H), 4.78-4.62 (m,1H), 4.61-4.44 (m, 2.5H), 4.26-4.12 (m, 1H), 4.12-4.00 (m, 0.5H),3.79-3.63 (m, 0.5H), 3.27-3.11 (m, 1H), 3.08-2.93 (m, 0.5H), 2.32 (s,3H), 2.31-2.20 (m, 1H), 2.17-2.05 (m, 1H), 2.01-1.85 (m, 1H), 1.69-1.49(m, 1H).

Example 85:N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethoxy)benzamide[4-[[[4-Fluoro-2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronicacid

Following procedure A, [4-(aminomethyl)phenyl]boronic acid hydrochloride(230 mg, 1.23 mmol) and 4-fluoro-2-(trifluoromethoxy)benzoic acid (0.24mL, 1.12 mmol) afforded the title compound (300 mg, 0.42 mmol, 38%yield) as a yellow solid.

UPLC-MS (ES⁺, Short acidic): 1.71 min, m/z 358.0 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[[4-fluoro-2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[[4-fluoro-2-(trifluoromethoxy)benzoyl]amino]methyl]phenyl]boronicacid (0.11 mL, 0.34 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(100 mg, 0.23 mmol) gave the title compound (114 mg, 0.18 mmol, 80%yield) as an orange foam.

UPLC-MS (ES⁺, Short acidic): 1.83 min, m/z 630[M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethoxy)benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(2-fluoro-5-methyl-benzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(229 mg, 0.41 mmol) gave the title compound (93 mg, 0.18 mmol, 97%yield) as a white foam.

UPLC-MS (ES⁺, Short acidic): 1.30 min, m/z 530.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethoxy)benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethoxy)benzamide(107 mg, 0.20 mmol) and acrylic acid (0.01 mL, 0.20 mmol) gave the titlecompound (13 mg, 0.02 mmol, 10% yield)

UPLC-MS (ES⁺, Short acidic): 1.51 min, m/z 584.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.39 min, m/z 584.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.08 (t, J6.0 Hz, 1H, NH), 8.27 (s, 1H, ArH), 7.73 (dd, J 8.5, 6.5 Hz, 1H, ArH),7.67-7.61 (m, 2H, ArH), 7.53-7.46 (m, 3H, ArH), 7.40 (td, J 8.5, 2.5 Hz,1H, ArH), 6.93-6.65 (m, 1H), 6.18-6.01 (m, 1H), 5.74-5.54 (m, 1H),4.80-4.64 (m, 1H), 4.60-4.47 (m, 2.5H), 4.25-4.14 (m, 1H), 4.11-4.01 (m,0.5H), 3.77-3.65 (m, 0.5H), 3.28-3.14 (m, 1H), 3.08-2.95 (m, 0.5H),2.31-2.21 (m, 1H), 2.18-2.07 (m, 1H), 1.99-1.86 (m, 1H), 1.69-1.47 (m,1H).

Example 86:N-[[4-[4-Amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol) in DCM (2 mL) was added triethylamine (0.05 mL, 0.33mmol), followed by trans-4-dimethylaminocrotonic acid hydrochloride (22mg, 0.13 mmol) and EDCl (31 mg, 0.16 mmol). The reaction mixture wasthen stirred at 25° C. for 16 h, quenched with a saturated solution ofNH₄Cl and extracted with DCM. The combined organics were dried overNa₂SO₄ and concentrated in vacuo. Further purification by mass-directpreparative LC-MS yieldedN-[[4-[4-amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2-enoyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(21 mg, 0.04 mmol, 33% yield) as a white solid.

UPLC-MS (ES⁺, Long acidic): 2.64 min, m/z 569.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.2 Hz, 1H, NH), 8.25 (s, 1H, ArH), 7.77 (dd, J 7.6, 1.7 Hz, 1H, ArH),7.66-7.61 (m, 2H, ArH), 7.53-7.45 (m, 3H, ArH), 7.18-7.14 (m, 1H, ArH),7.05 (td, J 7.6, 1.0 Hz, 1H, ArH), 6.75-6.44 (m, 2H), 4.77-4.63 (m, 1H),4.62-4.48 (m, 2.5H), 4.20-3.97 (m, 1.5H), 3.91 (s, 3H), 3.78-3.66 (m,0.5H), 3.29-2.94 (m, 1.5H), 2.30-2.03 (m, 7H), 2.02-1.87 (m, 3H),1.71-1.51 (m, 1H).

Example 87:N-[[4-[4-amino-1-[(3R)-1-[(E)-but-2-enoyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-[(E)-but-2-enoyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(21 mg, 0.04 mmol, 37% yield) as a white solid.

UPLC-MS (ES⁺, Long acidic): 3.25 min, m/z 526.5 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.77 (dd, J 7.6, 1.7 Hz, 1H, ArH),7.67-7.61 (m, 2H, ArH), 7.54-7.45 (m, 3H, ArH), 7.18-7.14 (m, 1H, ArH),7.04 (td, J 7.6, 1.0 Hz, 1H, ArH), 6.76-6.49 (m, 2H), 6.47-6.31 (m,0.5H), 4.76-4.62 (m, 1H), 4.62-4.46 (m, 2.5H), 4.24-4.02 (m, 1.5H), 3.91(s, 3H), 3.78-3.64 (m, 0.5H), 3.23-3.08 (m, 1H), 3.04-2.92 (m, 0.5H),2.29-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.96-1.89 (m, 1H), 1.89-1.67 (m,3H), 1.64-1.47 (m, 1H).

Example 88:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide[4-[[(5-Fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (0.41 g, 2.20 mmol) and 5-fluoropyridine-2-carboxylic acid(0.27 mL, 2.00 mmol) gave[4-[[(5-fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid (0.31g, 1.13 mmol, 57% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.25 min, m/z 274.9 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(5-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(5-fluoropyridine-2-carbonyl)amino]methyl]phenyl]boronic acid (185mg, 0.68 mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) gave tert-butyl(3R)-3-[4-amino-3-[4-[[(5-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(333 mg, 0.61 mmol assumed quantitative) as a brown solid, which wasused as such for the next step.

UPLC-MS (ES⁺, Short acidic): 2.04 min, m/z 547.3 [M+H]⁺

N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(5-fluoropyridine-2-carbonyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(333 mg, 0.61 mmol) gaveN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide(198 mg, 0.44 mmol, 72% yield) as a brown foam.

UPLC-MS (ES⁺, Short acidic): 1.12 min, m/z 447.2 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide(198 mg, 0.44 mmol) gaveN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide(47 mg, 0.09 mmol, 21% yield) as a white solid

UPLC-MS (ES⁺, Long acidic): 3.02 min, m/z 501.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.40 (t, J6.4 Hz, 1H, NH), 8.68 (d, J 2.8 Hz, 1H, ArH), 8.25 (s, 1H, ArH),8.17-8.13 (m, 1H, ArH), 7.92 (td, J 8.8, 2.8 Hz, 1H, ArH), 7.65-7.59 (m,2H, ArH), 7.52-7.47 (m, 2H, ArH), 6.93-6.64 (m, 1H), 6.18-6.00 (m, 1H),5.74-5.53 (m, 1H), 4.78-4.63 (m, 1H), 4.62-4.48 (m, 2.5H), 4.25-4.12 (m,1H), 4.11-4.00 (m, 0.5H), 3.75-3.65 (m, 0.5H), 3.25-3.12 (m, 1H),3.06-2.94 (m, 0.5H), 2.31-2.19 (m, 1H), 2.16-2.06 (m, 1H), 1.97-1.86 (m,1H), 1.67-1.50 (m, 1H).

Example 89:N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide[4-[[(3,5-Dimethylbenzoyl)amino]methyl]phenyl]boronic acid

Following general procedure A, [4-(aminomethyl)phenyl]boronic acidhydrochloride (410 mg, 2.20 mmol) and 3,5-dimethylbenzoic acid (300 mg,2.00 mmol) afforded[4-[[(3,5-dimethylbenzoyl)amino]methyl]phenyl]boronic acid (370 mg, 1.31mmol, 65% yield) as a colourless solid.

UPLC-MS (ES⁺, Short acidic): 1.45 min, m/z 284.1 [M+H]⁺

tert-Butyl(3R)-3-[4-amino-3-[4-[[(3,5-dimethylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D,[4-[[(5-dimethylbenzoyl)amino]methyl]phenyl]boronic acid (0.18 mL, 0.68mmol) and tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(200 mg, 0.45 mmol) afforded tert-butyl(3R)-3-[4-amino-3-[4-[[(3,5-dimethylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(210 mg, 0.38 mmol, 83% yield) as an orange foam.

UPLC-MS (ES⁺, Short acidic): 1.81 min, m/z 556.6 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide

Following general procedure E, tert-butyl(3R)-3-[4-amino-3-[4-[[(3,5-dimethylbenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(210 mg, 0.38 mmol) affordedN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide(160 mg, 0.35 mmol, 92% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.28 min, m/z 456.4 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide(187 mg, 0.41 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide(35 mg, 0.07 mmol, 17%) as a white solid.

UPLC-MS (ES⁺, Short acidic): 1.51 min, 510.3 m/z M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.37 min, 510.4 m/z [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.00 (t, J6.0 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.67-7.61 (m, 2H, ArH), 7.56-7.45(m, 4H, ArH), 7.17 (s, 1H, ArH), 6.92-6.65 (m, 1H), 6.18-6.01 (m, 1H),5.75-5.54 (m, 1H), 4.79-4.62 (m, 1H), 4.60-4.48 (m, 2.5H), 4.26-4.14 (m,1H), 4.12-4.01 (m, 0.5H), 3.76-3.63 (m, 0.5H), 3.27-3.12 (m, 1H),3.07-2.94 (m, 0.5H), 2.32 (s, 6H), 2.30-2.19 (m, 1H), 2.16-2.06 (m, 1H),1.97-1.87 (m, 1H), 1.68-1.48 (m, 1H).

Example 90:N-[[4-[4-Amino-1-(1-prop-2-enoyl-3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamidetert-Butyl3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure D, tert-butyl3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(127 mg, 0.29 mmol) and[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]boronic acid (129 mg, 0.43mmol) gave tert-butyl3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(274 mg, 0.39 mmol, assumed quantitative) as a light beige foam.

LC-MS (ES⁺, Short acidic): 1.84 min, m/z 564.2 [M+H]⁺

N-[[4-[4-Amino-1-(3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure E, tert-butyl3-[4-amino-3-[4-[[(2,5-difluorobenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(274 mg, 0.39 mmol) gaveN-[[4-[4-amino-1-(3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(0.11 g, 0.25 mmol, 63% yield) as an off-white foam.

LC-MS (ES⁺, Short acidic): 0.90 min, m/z 464.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆): 9.08-9.01 (m, 1H), 8.24 (s, 1H), 7.67-7.61(m, 2H), 7.53-7.46 (m, 3H), 7.44-7.35 (m, 1H), 4.73-4.63 (m, 1H), 4.55(d, J 6.0 Hz, 2H), 3.12-3.03 (m, 1H), 2.99-2.87 (m, 2H), 2.61-2.38 (m,2H), 2.16-2.06 (m, 1H), 2.06-1.97 (m, 1H), 1.80-1.71 (m, 1H), 1.63-1.50(m, 1H).

N-[[4-[4-Amino-1-(1-prop-2-enoyl-3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide

Following general procedure F,N-[[4-[4-amino-1-(3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(114 mg, 0.25 mmol) and acrylic acid (0.02 mL, 0.23 mmol) gaveN-[[4-[4-amino-1-(1-prop-2-enoyl-3-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide(53 mg, 0.10 mmol, 42% yield).

UPLC-MS (ES⁺, Short acidic): 1.41 min, m/z 518.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.12 min, m/z 518.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 9.05 (t, J5.7 Hz, 1H, NH), 8.26 (s, 1H, ArH), 7.65 (d, J 7.9 Hz, 2H, ArH), 7.51(d, J 7.9 Hz, 2H), 7.52-7.46 (m, 1H, ArH), 7.44-7.35 (m, 2H, ArH), 6.87(dd, J 16.5 Hz, J 10.5 Hz, 0.5H), 6.72 (dd, J 16.5 Hz, J 10.5 Hz, 0.5H),6.13 (d, J 16.5 Hz, 0.5H), 6.06 (d, J 16.5 Hz, 0.5H), 5.71 (d, J 10.5Hz, 0.5H), 5.58 (d, J 10.5 Hz, 0.5H), 4.80-4.63 (m, 1H), 4.56 (d, J 5.7Hz, 2H), 4.62-4.48 (m, 0.5H), 4.27-4.14 (m, 1H), 4.12-4.01 (m, 0.5H),3.78-3.64 (m, 0.5H), 3.28-3.12 (m, 1H), 3.08-2.95 (m, 0.5H), 2.34-2.19(m, 1H), 2.18-2.06 (m, 1H), 1.99-1.87 (m, 1H), 1.69-1.50 (m, 1H).

Example 91:N-[[4-[4-amino-1-[(3R)-1-(2,3-dihydroxypropanoyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideN-[[4-[4-Amino-1-[(3R)-1-(2,3-dihydroxypropanoyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a stirred solution ofN-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(119 mg, 0.23 mmol) in tert-butanol (3.2 mL) and pyridine (0.02 mL, 0.23mmol) was added a 2.5 wt % osmium tetroxide solution (80 mg, 0.31 mmol).The reaction was placed under a nitrogen atmosphere and was left to stirat room temperature for 18 h, quenched with a saturated NaHSO₃ solutionand was left to stir for an additional 1 h. The aqueous mixture wasextracted with EtOAc (×3). The combined organic extracts were driedthrough a phase separator and the filtrate concentrated under reducedpressure. Further purification by flash column chromatography (DCM/MeOH100:0 to 90:10) gaveN-[[4-[4-amino-1-[(3R)-1-(2,3-dihydroxypropanoyl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(17 mg, 0.03 mmol, 12% yield) as white solid.

UPLC-MS (ES⁺, Short acidic): 1.26 min, m/z 546.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.77 min, m/z 546.2 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.77 (t, J6.1 Hz, 1H, NH), 8.28-8.24 (m, 1H, ArH), 7.77 (dd, J 7.7, 1.8 Hz, 1H,ArH), 7.67-7.62 (m, 2H, ArH), 7.54-7.45 (m, 3H, ArH), 7.18-7.13 (m, 1H,ArH), 7.05 (td, J 7.7, 1.0 Hz, 1H, ArH), 5.08-4.97 (m, 0.5H), 4.93-4.74(m, 1H), 4.73-4.63 (m, 1H), 4.62-4.48 (m, 2.5H), 4.44-4.20 (m, 2H),4.14-4.03 (m, 0.5H), 3.91 s, 3H), 3.65-3.36 (m, 3H), 3.20-3.02 (m,1.5H), 2.86-2.69 (m, 0.5H), 2.30-2.15 (m, 1H), 2.16-2.05 (m, 1H),1.94-1.79 (m, 1H), 1.74-1.44 (m, 1H).

Example 92:N-[[4-[4-amino-1-[(3R)-1-but-2-ynoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol) and but-2-ynoic acid (9 mg, 0.11 mmol) affordedN-[[4-[4-amino-1-[(3R)-1-but-2-ynoyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(14 mg, 0.02 mmol, 23% yield).

UPLC-MS (ES⁺, Short acidic): 1.43 min, m/z 524.4 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 3.23 min, m/z 524.4 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 mixture of conformers) 8.80-8.73(m, 1H, NH), 8.26 (s, 0.5H, ArH), 8.25 (s, 0.5H, ArH), 7.79-7.74 (m, 1H,ArH), 7.67-7.62 (m, 2H, ArH), 7.54-7.44 (m, 3H, ArH), 7.19-7.13 (m, 1H,ArH), 7.08-7.01 (m, 1H, ArH), 4.84-4.74 (m, 0.5H), 4.71-4.62 (m, 0.5H),4.59 (d, J 6.0 Hz, 2H), 4.45-4.37 (m, 0.5H), 4.34-4.28 (m, 0.5H),4.26-4.18 (m, 0.5H), 4.05-3.97 (m, 0.5H), 3.91 (s, 3H), 3.84-3.77 (m,0.5H), 3.32-3.24 (m, 2H), 3.14-3.06 (m, 0.5H), 2.30-2.19 (m, 1H),2.17-2.08 (m, 1H), 2.05 (s, 1.5H), 2.01-1.92 (m, 1H), 1.84 (s, 1.5H),1.71-1.48 (m, 1H).

Example 93:N-[[4-[4-amino-1-[(3R)-1-(oxetan-3-yl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

A three-neck flask, fitted with a condenser and a bleach (6% w/v)scubber was charged withN-[[4-[4-amino-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(50 mg, 0.11 mmol), methanol (2.2 mL), 3-oxetanone (0.01 mL, 0.12 mmol),zinc chloride (57 mg, 0.42 mmol) and sodium cyanoborohydride (25 mg,0.39 mmol). The reaction mixture was heated to 50° C. and stirred atthis temperature for 16 h, quenched with water (10 mL) and extractedwith DCM (3×10 mL). The organics were passed through a phase separatorand concentrated in vacuo. The residue was purified by flash columnchromatography (0-15% MeOH in DCM) and filtration over SCX cartridge toaffordN-[[4-[4-amino-1-[(3R)-1-(oxetan-3-yl)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(15 mg, 0.03 mmol, 27% yield).

UPLC-MS (ES⁺, Short acidic): 1.16 min, m/z 514.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.59 min, m/z 514.3 [M+H]⁺

¹H NMR (400 MHz, MeOH-d₄) δ (ppm) 8.24 (s, 1H, ArH), 7.91 (dd, J 7.8,1.8 Hz, 1H, ArH), 7.67-7.63 (m, 2H, ArH), 7.58-7.47 (m, 3H, ArH),7.18-7.14 (m, 1H, ArH), 7.07 (td, J 7.8, 1.0 Hz, 1H, ArH), 4.99-4.89 (m,1H), 4.72-4.66 (m, 3H), 4.65-4.58 (m, 3H), 3.98 (s, 3H), 3.64-3.55 (m,1H), 3.28-3.14 (m, 1H), 3.01-2.94 (m, 1H), 2.85-2.75 (m, 1H), 2.53-2.35(m, 1H), 2.16-2.05 (m, 2H), 2.00-1.75 (m, 2H).

Example 94:N-[[4-[4-amino-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide3-Iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine

To a stirred solution of tert-butyl(3R)-3-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(500 mg, 1.13 mmol) in methanol (15 mL) was added hydrogen chloride in1,4-dioxane (4 M, 0.78 mL, 22.51 mmol). The reaction was stirred at roomtemperature for 14 h then the solvent was removed under reducedpressure. Further purification by flash column chromatography (DCM/7 NNH₃ in MeOH 100:0 to 90:10) gave3-iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (357 mg,0.93 mmol, 83% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 0.74 min, m/z 345.0 [M+H]⁺

3-Iodo-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine

To a stirred solution of3-iodo-1-[(3R)-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine (357 mg,1.04 mmol) and sodium triacetoxyborohydride (308 mg, 1.45 mmol) in DCM(30 mL) was added a formaldehyde solution (36.5-38%) in water (0.03 mL,1.14 mmol). The reaction mixture was stirred at room temperature for 16h. Additional formaldehyde solution (36.5-38%) in water (0.03 mL, 1.14mmol) was added. The mixture was stirred at room temperature for another2 h, quenched with a 5 M aqueous NaOH solution (10 mL) and concentratedunder reduced pressure. The white residue was then partitioned betweenwater (100 mL) and DCM (100 mL). The aqueous layer was extracted withDCM (3×100 mL). The combined organic extracts were then washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford3-iodo-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine(315 mg, 0.79 mmol, 76% yield) as a white solid.

UPLC-MS (ES⁺, Short acidic): 0.81 min, m/z 359.0 [M+H]⁺

N-[[4-[4-Amino-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure D,3-iodo-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-4-amine(100 mg, 0.28 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (119 mg, 0.42mmol) affordedN-[[4-[4-amino-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(30 mg, 0.06 mmol, 20% yield) as a brown solid.

UPLC-MS (ES⁺, Short acidic): 1.10 min, m/z 472.2 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.43 min, m/z 472.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.77 (t, J 6.0 Hz, 1H, NH), 8.24 (s,1H, ArH), 7.77 (dd, J 7.75, 1.8 Hz, 1H, ArH), 7.66-7.60 (m, 2H, ArH),7.53-7.45 (m, 3H, ArH), 7.18-7.14 (m, 1H, ArH), 7.40 (td, J 7.6, 1.0 Hz,1H, ArH), 4.83-4.62 (m, 1H), 4.59 (d, J 6.0 Hz, 2H), 3.91 (s, 3H),3.12-3.01 (m, 1H), 3.08-2.86 (m, 1H), 2.53-2.40 (m, 3H), 2.26-1.87 (m,4H), 1.84-1.71 (m, 1H), 1.69-1.48 (m, 1H).

Example 95:N-[[4-[4-Amino-1-(1-prop-2-enoyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]-methyl]-2-methoxy-benzamidetert-Butyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

To a stirred solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine(5.61 g, 21.5 mmol) and tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate (6.61 g, 23.65 mmol) in DMF(80 mL) under a nitrogen atmosphere was added cesium carbonate (16.11 g,49.44 mmol). The reaction mixture was heated to 70° C. and stirredfurther for 16 h at that temperature. The reaction mixture was cooled,concentrated under reduced pressure. The residue was taken up with EtOAc(100 mL) and water (200 mL) and sonicated for 25 min. The layers werepartitioned. The aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic extracts were washed with brine (2×100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give anorange solid. Further purification by flash column chromatography(DCM/EtOAc 1:1) gave tert-butyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(2.94 g, 6.62 mmol, 31% yield) as a pale orange solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.20 (s, 1H, ArH), 4.87-4.75 (m, 1H),4.14-3.98 (m, 2H), 3.07-2.80 (m, 2H), 1.98-1.80 (m, 2H).

tert-Butyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Following general procedure C, tert-butyl4-(4-amino-3-iodo-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate(2.92 g, 6.57 mmol) and[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (2.90 g, 9.86mmol) gave tert-butyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(2.63 g, 4.72 mmol, 72% yield) as a light beige foam.

LC-MS (ES⁺, Short acidic): 3.42 min, m/z 558.3 [M+H]⁺

N-[[4-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamidehydrochloride

Following general procedure E, tert-butyl4-[4-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate(2.63 g, 4.72 mmol) gave, after trituration with a mixture of MeOH/Et₂O,N-[[4-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamidehydrochloride (1.76 g, 3.56 mmol, 75% yield) as an off-white solid.

UPLC-MS (ES⁺, Short acidic): 1.03 min, m/z 458.3 [M+H]⁺

N-[[4-[4-Amino-1-(1-prop-2-enoyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Following general procedure F,N-[[4-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(100 mg, 0.22 mmol) and acrylic acid (20 μL, 0.22 mmol) gaveN-[[4-[4-amino-1-(1-prop-2-enoyl-4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(22 mg, 0.04 mmol, 19% yield) as a white powder.

UPLC-MS (ES⁺, Short acidic): 1.28 min, m/z 512.3 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.93 min, m/z 512.3 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm, 1:1 cis and trans mixture) 8.76 (t, J6.1 Hz, 1H, NH), 8.25 (s, 1H, ArH), 7.76 (dd, J 7.7, 1.8 Hz, 1H, ArH),7.66-7.61 (m, 2H, ArH), 7.52-7.45 (m, 3H, ArH), 7.18-7.14 (m, 1H), ArH),7.04 (td, J 7.7, 1.0 Hz, 1H, ArH), 6.87 (dd, J 16.6, 10.5 Hz, 1H), 6.13(dd, J 16.6, 2.4 Hz, 1H), 5.69 (dd, J 10.5, 2.4 Hz, 1H), 5.06-4.96 (m,1H), 4.58 (d, J 6.0 Hz, 2H), 4.57-4.50 (m, 1H), 4.26-4.15 (m, 1H), 3.91(s, 3H), 2.99-2.85 (m, H), 2.13-1.93 (m, 4H).

Example 96:N-[[4-[4-Amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamideN-[[4-[4-Amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

To a solution ofN-[[4-[4-amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide(96 mg, 0.21 mmol) in DCM (5 mL) was added a formaldehyde solution(36.5-38%) in water (0.03 mL, 0.23 mmol) and sodiumtriacetoxyborohydride (89 mg, 0.42 mmol). The reaction was placed undera nitrogen atmosphere and allowed to stir at room temperature overnight.NaOH (5 M, 15 mL) was added and the mixture stirred for 15 min. Themixture was concentrated to dryness. The solid residue was taken up inDCM and washed with water. The combined organic layer was dried overNa₂SO₄ and the solvent removed under reduced pressure. Furtherpurification by flash chromatography afforded the title product as awhite solid (35 mg, 0.07 mmol 34% yield).

LC-MS (ES⁺, Short acidic): 2.37 min, m/z 472.1 [M+H]⁺

LC-MS (ES⁺, Short acidic): 2.42 min, m/z 472.1 [M+H]⁺

UPLC-MS (ES⁺, Long acidic): 2.34 min, m/z 472.1 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 8.77 (t, J 6.1 Hz, 1H, NH), 8.24 (s,1H, ArH), 7.77 (dd, J 7.6, 1.7 Hz, 1H, ArH), 7.66-7.62 (m, 2H, ArH),7.53-7.46 (m, 3H, ArH), 7.18-7.14 (m, 1H), ArH), 7.04 (td, J 7.6, 1.0Hz, 1H, ArH), 4.70-4.61 (m, 1H), 4.58 (d, J 6.0 Hz, 2H), 3.91 (s, 3H),3.00-2.88 (m, 2H), 2.28 (s, 3H), 2.25-2.08 (m, 4H), 1.94-1.86 (m, 2H).

Example 97: BTK Binding Affinity

BTK binding affinity of each compound tested was determined using atime-resolved fluorescence resonance energy transfer (TR-FRET)methodology. 2.5 nM Recombinant BTK kinase, varying concentrations ofinhibitor, 2 nM LanthaScreen™ Eu anti-His Antibody and 15 nM KinaseTracer 236 was incubated in 1× LanthaScreen™ Kinase Buffer A for fivehours. Recombinant BTK kinase and all LanthaScreen™ components werepurchased from Invitrogen. Measurements were performed in a reactionvolume of 30 μL using half-area 96-well assay plates. The TR-FRET signalwas read on a plate reader with an excitation wavelength of 340 nm anddetection wavelengths of 615 and 665 nm. Binding affinity was determinedfor each compound by measuring TR-FRET signal at various concentrationsof compound and plotting the relative fluorescence units against theinhibitor concentration to estimate the IC₅₀ from log [Inhibitor] vsresponse using the Variable Slope model in Graphpad prism from Graphpadsoftware (SanDiego, Calif.).

Results of the BTK Binding Affinity are shown below in Table 3.

Table 3 shows the BTK Binding affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theBTK IC₅₀ value of the compound as“+”, “++”, “+++” and “++++”. Thecategory“+” refers to compounds with a BTK IC₅₀ of 10 nM to 100 nM. Thecategory“++” refers to compounds with a BTK IC₅₀ of 1 nM to 10 nM. Thecategory“+++” refers to compounds with a BTK IC₅₀ of 0.5 nM to 1 nM. Thecategory“++++” refers to compounds with a BTK IC₅₀ of <0.5 nM.

Example 98: EGFR Binding Affinity

EGFR binding affinity was determined using a time-resolved fluorescenceresonance energy transfer (TR-FRET) methodology. 2.5 nM RecombinantEGFR, varying concentrations of inhibitor, 2 nM LanthaScreen™ Euanti-GST Antibody and 3 nM Kinase Tracer 199 was incubated in 1×LanthaScreen™ Kinase Buffer A for five hours. Recombinant EGFR and allLanthaScreen™ components were purchased from Invitrogen. Measurementswere performed in a reaction volume of 30 μL using half-area 96-wellassay plates. The TR-FRET signal was read on a plate reader with anexcitation wavelength of 340 nm and detection wavelengths of 615 and 665nm. Binding affinity was determined for each compound by measuringTR-FRET signal at various concentrations of compound and plotting therelative fluorescence units against the inhibitor concentration toestimate the IC₅₀ from log [Inhibitor] vs response using the VariableSlope model in Graphpad prism from Graphpad software (SanDiego, Calif.).

Results of the EGFR binding affinity are shown in Table 3 below.

Table 1 shows the EGFR Binding Affinity, as determined by the assaydescribed above, for compounds of formula (I), categorised based on theEGFR IC₅₀ value of the compound as“*”, “**” and“***”. The category“*”refers to compounds with an EGFR IC₅₀ of >80 nM. The category“**” refersto compounds with an EGFR IC₅₀ of 25 to 80 nM. The category“***” refersto compounds with an EGFR IC₅₀ of <25 nM. A cell containing “n.f.”indicates that there was no fit for the compound in the assay.

Example 99: TMD8 Growth Assay

Compounds were assayed for effects on the growth of TMD8 human DLBCLcells that are dependent on NFκB signalling. TMD8 cells were grown insuspension in T225 flasks, centrifuged and re-suspended in 2.5% FBScontaining media. Cells were then plated at 1.0×10⁴ cells per well in96-well plates in varying concentrations of compound and incubated for72 hours at 37° C. An additional plate of cells to be used as the Day 0read was seeded without compound addition, Resazurin was added to eachwell, incubated for 5 h and the fluorescence measured at 590 nm. After72 h of compound treatment, Resazurin was added to each well of thecompound treated plates, incubated for 5 hours and the fluorescencemeasured at 590 nm. The IC₅₀ was then calculated but subtracting theaverage Day 0 value from each well value from the treated plates, eachtreatment was then calculated as a percentage of the DMSO control andthe percentages plotted against the inhibitor concentration to estimatethe IC₅₀ from log [Inhibitor] vs response using the Variable Slope modelin Graphpad prism from Graphpad software (San Diego, Calif.).

The results of the TMD8 growth assay are shown in Table 3 below.

Table 3 shows the TMD8 anti-proliferative activity, as determined by theassay described above, for compounds of formula (I), categorised basedon the TMD8 IC₅₀ value of the compound as “x”, “xx” and “xxx”. Thecategory “x” refers to compounds with a TMD8 IC₅₀ of 25 to 300 nM. Thecategory “xx” refers to compounds with a TMD8 IC₅₀ of 5 to 25 nM. Thecategory “xxx” refers to compounds with a TMD8 IC₅₀ of <5 nM. A “−”indicates that no testing has been carried out.

TABLE 3 BTK EGFR IC50 ID. Binding Binding TMD8 No. Name IC50 (nM) IC50(nM) (nM) 1 N-[[4-[4-amino-1-[(3R)-1-cyano-3-pipendyl]pyrazolo[3,4- ++n.f. x d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide 2N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ * xxpipendyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethyl)benzamide 3N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ * xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4,5-trifluoro-benzamide 4 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methyl-benzamide 5 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++++ ** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide 6 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++++ *** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide 7 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-benzamide 8 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide 9 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** x piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-cyano-benzamide 10 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide 11 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++ *** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methyl-benzamide 12 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-methoxy-benzamide 13 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ **xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide 14 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ *** xxxpiperidyl]-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-2-methoxy-benzamide 15 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-+++ ** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide 16 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-+++ *** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-2-methoxy-benzamide 17N-[[4-[4-amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4- ++++ n.d. xxxd]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 18N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ * xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethoxy-benzamide 19 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++*** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide 20 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-+++ ** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide 21 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++++ *** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide 22 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++*** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-tert-butyl-benzamide 23 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++*** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide 24 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-benzamide 25 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-(trifluoromethyl)benzamide 26N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 27 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ ** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,4-difluoro-benzamide 28 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3- yl]phenyl]methyl]benzamide29 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide 30 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ *** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethoxy)benzamide 31 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-+++ *** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methyl-benzamide 32 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ *** xxxpiperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-benzamide 33 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methoxy-benzamide 34 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-+++ *** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-2-carboxamide 35N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- + * xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-pyridine-4-carboxamide 36N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-(trifluoromethyl)benzamide 37N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-chloro-benzamide 38 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-chloro-5-(trifluoromethyl)benzamide 39N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-(trifluoromethyl)benzamide 40N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++ *** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-fluoro-benzamide 41 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ * xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-methoxybenzamide 42 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++ * x piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-3-(trifluoromethyl)benzamide 43N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-(trifluoromethyl)benzamide 44N-[[4-[4-amino-1-[(3R)-1-cyano-3-piperidyl]pyrazolo[3,4- ++++ * xxxd]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2- methoxybenzamide 45N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++ * xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-6-methylbenzamide 46 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++*** xx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-bis(trifluoromethyl)benzamide 47N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-methoxy-benzamide 48 N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-+++ ** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide 49 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-+++ *** xxx piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethoxy)benzamide 50 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-++++ *** xxx piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-chloro-2-methoxy-benzamide 51 N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3-++ *** xxx piperidyl]pyrazolo-[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-(trifluoromethyl)benzamide 52N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- ++++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-(trifluoromethyl)benzamide 53N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-difluoro-benzamide 54 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++*** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,3-difluoro-benzamide 55N-[[4-[4-Amino-1-(4-piperidyl)pyrazolo[3,4-d]pyrimidin-3- + * −yl]phenyl]methyl]-2-methoxy-benzamide 56N-[[4-[4-Amino-1-(1-prop-2-enoyl-4- ++ * −piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 57N-[[4-[4-Amino-1-[(3R)-1-methyl-3-piperidyl]pyrazolo[3,4- ++ * −c]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 58N-[[4-[4-Amino-1-[(3R)-1-(oxetan-3-yl)-3- + * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 59 N-[[4-[4-Amino-1-[(3R)-1-but-2-ynoyl-3- +++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 60N-[[4-[4-Amino-1-[(3R)-1-(2,3-dihydroxypropanoyl)-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 61 N-[[4-[4-Amino-1-(1-prop-2-enoyl-3- ++++ ** −piperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide 62 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++*** − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3,5-dimethyl-benzamide 63 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ **− piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-pyridine-2-carboxamide 64N-[[4-[4-Amino-1-[(3R)-1-[(E)-but-2-enoyl]-3- +++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 65N-[[4-[4-Amino-1-[(3R)-1-[(E)-4-(dimethylamino)but-2- ++++ * −enoyl]-3-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 66N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-2-(trifluoromethoxy)benzamide 67N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methyl-benzamide 68 N-[[4-[4-Amino-1-[(3R)-1-(2-cyanoethyl)-3-++ * − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 69 N-[[4-[4-Amino-1-[(3R)-1-(cyanomethyl)-3- + * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 70 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-N-methyl-benzamide 71N-[[4-[4-Amino-1-[(3R)-1-(2-cyanoacetyl)-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 72 N-[[4-[4-Amino-1-[(3R)-1-propanoyl-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 73 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ ** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-3-methyl-benzamide 74 N-[[5-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-+++ ** − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide 75N-[[5-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,5-difluoro-benzamide 76N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++++ *** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-(trifluoromethyl)benzamide 77N-[[4-[4-Amino-1-[(3R)-1-[[(2R)-oxiran-2-yl]methyl]-3- ++ ** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 78 N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide 79 N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++*** − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide 80 N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 81 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ * −piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-N-methyl-benzamide 82 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-++ * − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethyl)benzamide 83 N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-++ *** − piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,6-difluoro-benzamide 84 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ **− piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-methoxy-benzamide 85 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]-+++ * − pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-N-methyl-benzamide 86 N-[[4-[4-Amino-1-(1-prop-2-enoyl-3- +++ *** xxxpiperidyl)pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2-methoxy-benzamide 87N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-3-cyano-benzamide 88N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-4-fluoro-2-methoxy-benzamide 89N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluoro-phenyl]methyl]-2,6-difluoro-benzamide 90N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-ethoxy-3-(trifluoromethyl)benzamide 91N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide 92 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-+++ *** xxx piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methyl-benzamide 93 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- ++ *** xpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-4-methoxy-benzamide 94 N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-++ *** x piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-fluoro-3-(trifluoromethyl)benzamide 95N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ ** xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-6-(trifluoromethyl)benzamide 96N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3- +++ * xxxpiperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-5-methoxy-benzamide

The following table, Table 4, provides values of the BTK bindingefficacy of a selection of compounds of the invention.

TABLE 4 BTK ID. Binding No. Name IC50 (nM) 5N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.4piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-(trifluoromethoxy)benzamide 6N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.4piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-4-chloro-2-methoxy-benzamide 8N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.2piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-5-methyl-benzamide 13N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.4piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-3-cyano-benzamide 15N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.7piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-4-methyl-benzamide 23N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.4piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2,5-difluoro-benzamide 26N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.3piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide 29N-[[4-[4-amino-1-[(3R)-1-prop-2-enoyl-3- 0.4piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-fluoro-benzamide 48N-[[3-[4-Amino-1-[(3R)-1-prop-2-enoyl- 0.53-piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-5-fluoro-2-methoxy-benzamide 59N-[[4-[4-Amino-1-[(3R)-1-but-2-ynoyl-3- 0.8piperidyl]pyrazolo[3,4-d]pyrimidin-3-yl]phenyl]methyl]-2-methoxy-benzamide

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

The invention claimed is:
 1. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof, wherein A is N or CR^(a),D is either a substituted or unsubstituted C₁₋₆ alkylene chain which issaturated or unsaturated and which optionally contains, where chemicallypossible, 1, 2, or 3 N, O, or S atoms in the chain, wherein the N, O, orS atoms are independently chosen at each occurrence; or D represents asubstituted or unsubstituted carbocyclic or heterocyclic moiety which issaturated or unsaturated and which contains from 3 to 8 atoms in thecarbocyclic or heterocyclic ring, wherein the ring is optionallysubstituted with —NR^(b)—, wherein —NR^(b)— is bonded to the ring; andwherein, when substituted, the alkylene chain or the carbocyclic orheterocyclic moiety includes 1 to 5 substituents independently selectedat each occurrence from: halo, —OR^(b), —SR^(b), —NR^(b)R^(c), NO, ═O,—CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, —SO₂R^(b),SO₃R^(b), —C(O)R^(b), and C(O)OR^(b); E is selected from C₁₋₄ alkyl,and:

Y is either O or NR^(b); X is selected from H, methyl, and CN; L¹ isselected from a bond, —O—, —O(CR^(d)R^(e))_(m)—, —NR^(b)—, and—(CR^(d)R^(e))_(m)—; L² represents —NR^(b)C(O)—; n is selected from 1,2, and 3; m is selected from 1, 2, 3, and 4; o is selected from 0, 1, 2,3, and 4; R^(a) is selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,OH, SH, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, NR^(b)R^(c), —CN, acyl, —C(O)R^(b), —C(O)OR^(b),—SO₂R^(b), and —SO₃R^(b); R^(b) and R^(c) are independently selected ateach occurrence from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇cycloalkyl, and C₃₋₇ halocycloalkyl; R^(d) and R^(e) are independentlyselected at each occurrence from: H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl; R¹ is a groupselected from a substituted or unsubstituted carbocyclic or heterocyclicmoiety which either contains from 3 to 8 atoms in a single ring or 7 to14 atoms in a fused polycyclic ring system, wherein, when substituted,R¹ contains 1 to 5 substituents independently selected at eachoccurrence from halo, OR^(b), —SR^(b), —NR^(b)R^(c), —NO₂, ═O, —CN,acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, —SO₂R^(b), SO₃R^(b), —C(O)R^(b), —C(O)OR^(b),—C(O)NR^(b)R^(c), and aryl optionally substituted by 1 or 2 halo atoms;R² is selected from: H, halo, OR^(b), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl,—NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), and —C(O)NR^(b)R^(c); and R³, R⁴,and R⁵ are independently selected from: H, halo, —OR^(b), —CN,NR^(b)R^(c), —CH₂NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), —C(O)NR^(b)R^(c),C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl,C₁₋₆ alkyl substituted with C₃₋₈ heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈cycloalkenyl, C₃₋₈ heterocycloalkenyl, aryl, heteroaryl, alkaryl, andalkheteroaryl; or R³ and R⁴ taken together with the carbon atoms towhich they are attached form a C₃₋₈ cycloalkene, and R⁵ is independentlyselected from: H, halo, —OR^(b), —CN, —NR^(b)R^(c), —CH₂NR^(b)R^(c),—CO₂R^(b), —C(O)R^(b), —C(O)NR^(b)R^(c), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkyl substituted with C₃₋₈ cycloalkyl, C₁₋₆ alkyl substituted with C₃₋₈heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈, heterocycloalkenyl, aryl,heteroaryl, alkaryl, and alkheteroaryl; or R⁴ and R⁵ taken together withthe carbon atom to which they are attached form a C₃₋₈ cycloalkyl and R³is independently selected from: H, halo, —OR^(b), —CN, —NR^(b)R^(c),CH₂NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), —C(O)NR^(b)R^(c), C₁₋₆ alkoxy,C₁₋₆ alkyl, C₁₋₆ alkyl substituted with C₃₋₈ cycloalkyl, C₁₋₆ alkylsubstituted with C₃₋₈ heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl,C₃₋₈ heterocycloalkenyl, aryl, heteroary, alkaryl, and alkheteroaryl; orR³ and R⁵ taken together with the carbon atoms to which they areattached form a C—C triple bond and R⁴ is independently selected from:H, halo, —OR^(b), —CN, —NR^(b)R^(c), CH₂NR^(b)R^(c), —CO₂R^(b),—C(O)R^(b), —C(O)NR^(b)R^(c), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with C₃₋₈ cycloalkyl, C₁₋₆ alkyl substituted with C₃₋₈heterocycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈heterocycloalkenyl, aryl, heteroaryl, alkaryl, and alkheteroaryl.
 2. Acompound of claim 1, wherein A is CR^(a) and R^(a) is H, fluoro, chloro,or C₁₋₄ haloalkyl.
 3. A compound of claim 1, wherein R¹ is a substitutedor unsubstituted: C₃₋₈ cycloalkyl, C₆₋₁₄ aryl, or C₅₋₁₄ heteroaryl,wherein the C₃₋₈ cycloalkyl group is saturated or unsaturated, andwherein when substituted, R¹ contains 1, 2, or 3 substituentsindependently selected at each occurrence from: halo, —OR^(b), —SR^(b),—NR^(b)R^(c), NO₂, ═O, —CN, acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, C₃₋₈ heterocycloalkyl, —SO₂R^(b), SO₃R^(b), —C(O)R^(b),—C(O)OR^(b), —C(O)NR^(b)R^(c), and aryl optionally substituted by 1 or 2halo atoms.
 4. A compound of claim 1, wherein R¹ is unsubstituted phenylor phenyl substituted with 1, 2, or 3 substituents independentlyselected at each occurrence from: halo, —OR^(b), —CN, C₁₋₆ alkyl, andC₁₋₆ haloalkyl.
 5. A compound of claim 1, wherein n is
 1. 6. A compoundof claim 1, wherein R² is hydrogen.
 7. A compound of claim 1, whereinR³, R⁴, and R⁵ are independently selected from hydrogen, fluorine,chlorine, bromine, iodine, —CN, —CH₂NR^(b)R^(c), and C₁₋₆ alkyl, whereinR^(b) and R^(c) are independently selected from hydrogen and C₁₋₄ alkyl.8. A compound of claim 1, wherein R³, R⁴, and R⁵ are each hydrogen.
 9. Acompound of claim 1, wherein E is:


10. A compound of claim 1, wherein E is:


11. A compound of claim 1, wherein D is substituted or unsubstitutedC₃₋₈ heterocycloalkyl.
 12. A compound of claim 1, wherein D is


13. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof, wherein A is N or CR^(a);D is cyclopentyl; E is absent; L¹ is selected from a bond, —O—,—O(CR^(d)R^(e))_(m)—, —NR^(b)—, and —(CR^(d)R^(e))_(m)—; L² represents—NR^(b)C(O)—; n is selected from 1, 2, and 3; m is selected from 1, 2,3, and 4; R^(a) is selected from: H, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,OH, SH, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈cycloalkenyl, NR^(b)R^(c), —CN, acyl, —C(O)R^(b), —C(O)OR^(b),—SO₂R^(b), and —SO₃R^(b); R^(b) and R^(c) are independently selected ateach occurrence from: H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ acyl, C₃₋₇cycloalkyl, and C₃₋₇ halocycloalkyl; R^(d) and R^(e) are independentlyselected at each occurrence from: H, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ acyl, C₃₋₇ cycloalkyl, and C₃₋₇ halocycloalkyl; R¹ is a groupselected from a substituted or unsubstituted carbocyclic or heterocyclicmoiety which either contains from 3 to 8 atoms in a single ring or 7 to14 atoms in a fused polycyclic ring system, wherein, when substituted,R¹ contains 1 to 5 substituents independently selected at eachoccurrence from halo, OR^(b), —SR^(b), —NR^(b)R^(c), —NO₂, ═O, —CN,acyl, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl and C₃₋₈heterocycloalkyl, —SO₂R^(b), —SO₃R^(b); —C(O)R^(b), —C(O)OR^(b),—C(O)NR^(b)R^(c), and aryl optionally substituted by 1 or 2 halo atoms;R² is selected from: halo, OR^(b), C₁₋₆ alkoxy, C₁₋₆ alkyl, C₂₋₆alkynyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈ heterocycloalkenyl,—NR^(b)R^(c), —CO₂R^(b), —C(O)R^(b), and —C(O)NR^(b)R^(c).
 14. Acompound of claim 1, wherein L¹ is selected from a bond, —CH₂—, —O—, and—NH.
 15. A compound of claim 1, wherein the compound of formula (I) is acompound according to formula (VIIa) or (VIIb):

or a pharmaceutically acceptable salt thereof.
 16. A compound of claim1, wherein the compound of formula (I) is a compound selected from:

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition, wherein the pharmaceutical composition comprises a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable excipients.
 18. A pharmaceuticalcomposition of claim 17 wherein the composition comprises an additionalpharmaceutically active agent.
 19. A compound of claim 1, wherein A isCR^(a) and R^(a) is H.
 20. A compound of claim 1, wherein R¹ isunsubstituted phenyl or phenyl substituted with 1, 2, or 3 substituentsindependently selected at each occurrence from: fluoro, chloro, methoxy,—CN, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethoxy, and —OCF₃.21. A compound of claim 1, wherein D is substituted or unsubstituted C₆heterocycloalkyl.